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Protein aggregation

Protein aggregation is the process by which multiple protein molecules assemble into higher-order structures, such as soluble oligomers, insoluble fibrils, or amorphous aggregates, typically driven by non-native intermolecular interactions that arise from partial unfolding, misfolding, or phase separation of the proteins.^[1] This phenomenon is a fundamental aspect of protein behavior in living systems, influenced by factors including protein concentration, environmental conditions like pH and temperature, and intrinsic sequence properties that expose aggregation-prone regions.^[1] While aggregation can occur reversibly under physiological conditions, uncontrolled or pathological aggregation often leads to stable, dysfunctional complexes that disrupt cellular homeostasis.^[2] In biological contexts, protein aggregation plays essential roles in cellular organization and adaptation. For instance, proteins can form membraneless biomolecular condensates through liquid-liquid phase separation (LLPS), creating dynamic structures like stress granules that sequester RNAs and signaling molecules during cellular stress, thereby protecting and facilitating recovery in organisms such as yeast and mammals.^[3] These aggregates, ranging from liquid-like droplets to more solid amyloid fibers, also contribute to developmental processes, such as the formation of P granules in C. elegans embryos for germline specification, and functional amyloids like Pmel17 fibrils that support melanin synthesis in melanosomes.^[3] Regulation of these processes involves molecular chaperones, such as Hsp70 and Hsp100 families, which prevent unwanted aggregation or promote disaggregation via ATP-dependent mechanisms.^[3] Conversely, aberrant protein aggregation is a hallmark of numerous neurodegenerative diseases, where misfolded proteins form toxic inclusions that impair neuronal function and promote cell death.^[4] In Alzheimer's disease, aggregation of amyloid-β peptides into plaques and hyperphosphorylated tau into neurofibrillary tangles disrupts synaptic transmission and induces oxidative stress.^[4] Parkinson's disease features α-synuclein aggregates in Lewy bodies, which interfere with mitochondrial function and dopamine signaling, while Huntington's disease involves polyglutamine-expanded huntingtin protein forming intranuclear inclusions that alter gene expression.^[4] Amyotrophic lateral sclerosis is linked to aggregates of TAR DNA-binding protein-43 (TDP-43) and superoxide dismutase 1 (SOD1), contributing to motor neuron degeneration through prion-like propagation and proteostasis collapse.^[4] These pathological aggregates often resist degradation by cellular quality control systems, including the ubiquitin-proteasome pathway and autophagy-lysosome machinery, exacerbating disease progression.^[4] Beyond biology, protein aggregation poses significant challenges in biotechnology, particularly for therapeutic proteins, where even low levels of aggregates can trigger immunogenicity and reduce efficacy during storage or administration.^[1] Strategies to mitigate aggregation include engineering mutations to shield aggregation-prone regions and optimizing formulation conditions to enhance protein stability.^[2] Overall, understanding the dual nature of protein aggregation—beneficial in regulated forms and detrimental when dysregulated—remains crucial for advancing treatments for aggregation-related disorders and improving biopharmaceutical design.

Fundamentals

Definition and Overview

Protein aggregation refers to the abnormal association of misfolded or unfolded proteins into larger, often insoluble structures such as amyloid fibrils, plaques, or amorphous aggregates.^[5] This process typically arises from the exposure of hydrophobic regions in destabilized proteins, leading to self-association that bypasses normal folding pathways. The biophysical principles underlying protein aggregation are driven primarily by hydrophobic interactions, where non-polar residues cluster to minimize contact with the aqueous environment, supplemented by hydrogen bonding that stabilizes β-sheet-rich structures and van der Waals forces that contribute to close packing within aggregates.^[6] These non-covalent interactions facilitate the transition from soluble monomers to oligomeric intermediates and eventually to higher-order assemblies, with the hydrophobic effect often initiating the process by promoting partial unfolding.^[7] Early observations of amyloid deposits date to the mid-19th century, when Rudolph Virchow in 1854 coined the term "amyloid" to describe waxy tissue abnormalities exhibiting iodine staining similar to starch, based on light microscopy studies of pathological specimens.^[8] A key milestone came in 1959, when electron microscopy by Cohen and Calkins revealed the fibrillar ultrastructure of amyloid deposits, approximately 80–100 Å in width and of indeterminate length, shifting understanding toward protein-based fibril formation.^[8] Protein aggregation occurs across all organisms, from prokaryotes to eukaryotes, where it serves pathological roles in over 30 human diseases including neurodegenerative disorders, but also fulfills normal functions such as forming reversible inclusion bodies in bacteria under stress to sequester misfolded proteins temporarily.^[9]^[10] In higher eukaryotes, however, persistent aggregates often disrupt cellular homeostasis and contribute to toxicity. The kinetics of protein aggregation are commonly modeled using the nucleation-polymerization framework, which captures the lag phase of nucleus formation followed by rapid elongation. A basic form of this model describes the rate of change in aggregate concentration [A] as:

\frac{d[A]}{dt} = k_n [M]^n + k_e [A][M]

where [M] is the monomer concentration, k_n is the nucleation rate constant, n is the size of the critical nucleus, and k_e is the elongation rate constant; this equation highlights the concentration-dependent nucleation step and linear growth onto existing aggregates.^[11]

Types of Protein Aggregates

Protein aggregates can be broadly classified into amorphous and ordered types based on their structural organization, with each exhibiting distinct morphological properties, formation characteristics, and detection methods. Amorphous aggregates are disordered, non-fibrillar clumps that lack long-range order, often forming rapidly under denaturing conditions such as heat or chemical agents like high concentrations of urea or guanidine hydrochloride. These aggregates typically arise from partially folded intermediates exposing hydrophobic regions, leading to nonspecific associations, and they are prevalent in both in vitro refolding experiments and cellular overexpression systems.^[12]^[2] Ordered aggregates, in contrast, display highly structured architectures, most notably amyloid fibrils characterized by a cross-β-sheet conformation where β-strands align perpendicular to the fibril axis. These fibrils exhibit a characteristic X-ray diffraction pattern, including a 4.7 Å meridional reflection indicative of hydrogen-bonded β-strands and a 10-11 Å equatorial reflection from inter-sheet spacing. Amyloid fibrils are thermodynamically stable, insoluble without denaturants, and often 7-12 nm in diameter, composed of twisted protofilaments. Detection commonly relies on Thioflavin T (ThT) fluorescence, which increases upon binding to the cross-β structure, or Congo red birefringence under polarized light.^[13]^[12]^[14] Oligomers represent early, soluble intermediates in the aggregation pathway, typically comprising 10-100 protein molecules and enriched in β-sheet content, though heterogeneous in structure. These species, such as Aβ dimers or pentamers/hexamers, are often globular and more cytotoxic than mature fibrils due to their ability to interact with cellular membranes and disrupt function. Unlike fibrils, oligomers may form off-pathway and are detected using size-exclusion chromatography coupled with multi-angle light scattering (SEC-MALS) or fluorescence probes like aniline blue or pentameric thiophenyl (pFTAA) that bind β-sheets.^[15]^[13]^[2] Inclusion bodies are dense, cytoplasmic aggregates primarily observed in prokaryotic cells, such as Escherichia coli, during overexpression of recombinant proteins. Composed mainly of misfolded proteins with 50-70% native-like secondary structure but increased β-sheet content, these amorphous structures appear as refractile inclusions under phase-contrast microscopy and are insoluble, often requiring denaturation for recovery. Detection involves techniques like transmission electron microscopy (TEM) or attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy, which reveals β-sheet bands around 1623-1637 cm⁻¹.^[12]^[12] Prion aggregates exemplify infectious conformers, where a misfolded protein isoform, such as PrP^Sc, propagates by templating the conversion of native PrP^C into the pathogenic state, forming amyloid-like fibrils with in-register parallel β-sheets. These self-propagating structures underlie transmissible spongiform encephalopathies and are detected via cryo-electron microscopy (cryo-EM) or protein misfolding cyclic amplification (PMCA) assays that amplify the infectious conformer. Hybrid aggregates, involving co-aggregation of multiple proteins like Aβ and tau, further complicate morphology by mixing distinct misfolded species into shared β-sheet-rich assemblies.47636-7/fulltext)^[13]^[16] Amorphous aggregates are readily identified by their rapid onset without a lag phase and detection via turbidity measurements, where light scattering increases due to particle formation larger than the incident wavelength, or dynamic light scattering (DLS) for size distribution. In contrast, amyloid fibrils show a sigmoidal kinetic profile with a lag phase, confirmed by the specific 4.7 Å X-ray reflection diagnostic of cross-β ordering.^[17]^[18]^[13]

Causes and Mechanisms

Genetic and Mutational Factors

Genetic alterations, including point mutations and repeat expansions in protein-coding genes, can destabilize protein structures, promoting misfolding and subsequent aggregation. These mutations often alter key physicochemical properties such as hydrophobicity or charge, reducing the stability of the native fold and favoring aberrant intermolecular interactions. For instance, in sickle cell anemia, a point mutation in the β-globin gene substitutes glutamic acid with valine at position 6 (Glu6Val), introducing a hydrophobic residue that facilitates the polymerization of deoxygenated hemoglobin into rigid fibers under low-oxygen conditions.^[19] This change exemplifies how single amino acid substitutions can shift the thermodynamic balance toward aggregation-prone conformations.^[20] Repeat expansions, particularly of trinucleotide sequences, represent another critical mutational mechanism driving protein aggregation in neurodegenerative disorders. In Huntington's disease, expansion of CAG repeats in the huntingtin (HTT) gene beyond 36 units encodes an elongated polyglutamine tract in the HTT protein, exceeding a pathological threshold that promotes self-assembly into β-sheet-rich fibrils.^[21] This length-dependent aggregation is thought to arise from increased propensity for polyglutamine chains to form intermolecular hydrogen bonds, leading to insoluble inclusions that impair cellular function.^[22] Mutations affecting chaperone proteins or the folding machinery further exacerbate aggregation by impairing quality control mechanisms. For example, variants in BAG3, a co-chaperone that regulates HSP70-mediated refolding, disrupt the HSP70 network, causing accumulation of misfolded clients and widespread protein aggregates in myofibrillar myopathy.^[23] Such defects reduce the capacity for substrate recognition and ATP-dependent remodeling, allowing aggregation-prone intermediates to persist.^[24] Inheritance patterns of aggregation-related disorders often follow autosomal dominant transmission, where a single mutant allele suffices to confer risk. Familial transthyretin amyloidosis, caused by mutations in the TTR gene, exemplifies this, with over 100 variants leading to destabilized tetrameric transthyretin that dissociates and aggregates into amyloid fibrils in tissues like the heart and nerves.^[25] Similarly, in familial Alzheimer's disease, mutations in the amyloid precursor protein (APP) gene, such as the London mutation (Val717Ile), enhance Aβ peptide production or alter its aggregation kinetics, accelerating plaque formation.^[26] From an evolutionary perspective, the accumulation of deleterious mutations contributes to age-related protein aggregation vulnerability. Mutation accumulation theory posits that late-acting harmful variants, including those predisposing to proteostasis collapse, evade purifying selection due to reduced reproductive fitness pressure post-reproduction, leading to their buildup in aging populations.^[27] This somatic and germline accrual aligns with observed increases in protein misfolding during senescence, underscoring aggregation as a hallmark of evolutionary trade-offs in longevity.^[28]

Errors in Protein Synthesis and Folding

Errors in protein synthesis and folding represent a primary intrinsic cause of protein aggregation, distinct from sequence alterations due to mutations. During translation, the ribosome decodes mRNA into polypeptides, but inaccuracies such as tRNA misacylation—where aminoacyl-tRNA synthetases incorrectly charge tRNAs with non-cognate amino acids—can incorporate erroneous residues, leading to misfolded proteins prone to aggregation.^[29] Similarly, ribosomal stalling, often triggered by rare codons or damaged mRNA, exposes nascent chains to premature folding attempts, resulting in aberrant polypeptides that aggregate co-translationally.^[30] These translational defects increase the population of non-native conformers, which intermolecular interactions can stabilize into aggregates, as evidenced in studies of yeast and bacterial systems where stalling induces inclusion body formation.^[31] Co- and post-translational modifications further contribute to aggregation when dysregulated. Improper disulfide bond formation, catalyzed by oxidoreductases in the endoplasmic reticulum (ER), can lock proteins into non-native conformations if incorrect pairings occur, promoting misfolding and subsequent aggregation in secretory pathways.^[32] For instance, in neurodegenerative contexts, aberrant disulfide crosslinking in proteins like TDP-43 exacerbates amyloidogenic aggregation by stabilizing toxic oligomers.^[33] Likewise, errors in glycosylation, such as incomplete or hyper-glycosylation, disrupt the steric shielding that normally prevents hydrophobic exposure; hyper-glycosylation in recombinant systems has been shown to induce ER stress and aggregation by altering protein solubility.^[34] These modifications, intended to guide folding, instead create kinetic barriers when erroneous, leading to accumulation of aggregation-prone intermediates.^[35] Chaperone overload exacerbates these issues during high-expression scenarios, such as viral infections or recombinant production, where the demand for Hsp70/Hsp90 in eukaryotes or GroEL/GroES in prokaryotes outstrips availability. Hsp70 binds nascent chains to prevent premature collapse, but saturation allows unfolded domains to interact, forming aggregates; experiments in E. coli demonstrate that overexpressing aggregation-prone proteins depletes GroEL, resulting in up to 50% insoluble fractions.^[36] In vitro translation systems lacking chaperones further illustrate this: purified ribosomes synthesizing proteins like firefly luciferase yield rapid aggregation without Hsp70 addition, highlighting the essential role of chaperones in averting kinetic traps during folding.^[36] Failures in signal peptide cleavage also contribute to aggregation, particularly for ER-targeted proteins. The signal peptidase complex cleaves the N-terminal signal sequence post-translocation, but mutations or overload can leave uncleaved peptides, causing membrane anchoring defects and exposure of hydrophobic regions that drive oligomerization. In mammalian cells, uncleaved signal sequences in HLA class I molecules lead to ER retention and aggregation, mimicking inclusion bodies in disease states.^[37] Such errors compound translational inaccuracies, increasing the aggregate burden without invoking external stresses. The folding funnel concept, introduced by Wolynes and colleagues, provides a kinetic framework for these errors: proteins navigate a rugged energy landscape toward the native state, but mistranslation or modification defects deepen off-pathway traps, where partially folded states with exposed hydrophobics aggregate intermolecularly. In this model, the funnel's width reflects sequence-specific frustration, with translational errors narrowing productive paths and favoring kinetic arrest in aggregated minima, as simulated for helical bundle proteins. This theoretical lens underscores how synthesis fidelity maintains funnel smoothness, preventing the aggregation cascades observed in proteotoxic conditions.

Environmental and Cellular Stresses

Environmental and cellular stresses play a critical role in inducing protein misfolding and subsequent aggregation by disrupting the native conformational stability of proteins. Thermal stress, particularly heat shock, causes partial unfolding of proteins, exposing hydrophobic regions that promote intermolecular interactions and aggregation. For instance, acute heat stress in human cells leads to the reversible aggregation of nuclear proteins, including those involved in RNA processing, as a protective mechanism against denaturation. The rate of protein aggregation often exhibits a U-shaped temperature dependence, with minimal aggregation near physiological temperatures (around 37°C) due to optimal folding kinetics, increasing at both lower temperatures through cold-induced structural rigidification and higher temperatures via enhanced unfolding and collision rates. This non-Arrhenius behavior has been observed in the aggregation of human IgG1 Fc fragments, where rates accelerate below 40°C and above 60°C under neutral pH conditions.31366-8)^[38]^[39] Oxidative stress, arising from elevated reactive oxygen species (ROS), further exacerbates protein aggregation by chemically modifying vulnerable residues, such as cysteines, leading to the formation of disulfide-linked aggregates. ROS-induced oxidation of cysteine thiols can form aberrant disulfide bridges, stabilizing misfolded conformations and promoting oligomerization, as seen in various neurodegenerative contexts. In conditions like cerebral ischemia-reperfusion injury, oxidative stress triggers superoxide dismutase 1 (SOD1) aggregation in astrocytes through disulfide reduction and monomer formation, contributing to neuroinflammatory damage. These modifications not only impair protein function but also hinder clearance mechanisms, amplifying aggregate accumulation.^[40]^[41] Alterations in pH and ionic environments also drive protein aggregation, particularly in intracellular compartments like lysosomes where acidic conditions prevail. Low pH promotes amyloid formation by destabilizing soluble monomers, favoring β-sheet-rich fibril structures; for example, β-amyloid peptide (Aβ) rapidly assembles into toxic fibrils at pH 5.0–6.0, mimicking lysosomal acidity. Ionic imbalances, such as elevated salt concentrations, modulate electrostatic interactions, accelerating fibrillation of Aβ40 by screening repulsive charges between peptides. In lysosomal dysfunction, impaired acidification leads to incomplete proteolysis and aggregate buildup, underscoring the role of pH homeostasis in preventing amyloidogenic pathways.^[42] Chemical denaturants like urea and guanidine hydrochloride induce aggregation by disrupting non-covalent interactions essential for protein stability, including hydrogen bonds. Urea preferentially forms hydrogen bonds with the protein backbone, weakening intramolecular interactions and exposing aggregation-prone surfaces, while guanidine hydrochloride primarily acts through ionic disruption of salt bridges. These agents are commonly used in vitro to study unfolding pathways, revealing that intermediate denaturant concentrations often yield the highest aggregate levels due to partial unfolding without complete solubilization.^[43] In eukaryotic cells, endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which, if unresolved, leads to the accumulation of aggregate-prone proteins. ER stress from unfolded protein overload triggers UPR sensors like IRE1, PERK, and ATF6, aiming to restore proteostasis by upregulating chaperones; however, chronic activation promotes widespread aggregation beyond the ER, including cytosolic proteins forming prion-like structures. This response highlights how cellular stressors can propagate misfolding cascades, linking acute ER perturbations to broader proteotoxic events.^[44]^[45]

Contribution of Aging

Aging profoundly impacts proteostasis, the cellular network responsible for maintaining protein homeostasis, leading to a progressive collapse that favors protein aggregation. This decline manifests as reduced capacity to handle proteotoxic stress, with chaperone proteins playing a central role. Molecular chaperones, such as Hsp70, assist in protein folding and prevent misfolding; however, their expression and activity diminish over time. In humans, basal levels of Hsp70 decrease significantly with age, contributing to impaired stress responses and increased vulnerability to protein damage.^[46]^[47] This proteostasis collapse is exacerbated in senescent cells, where chaperone induction under heat stress is markedly reduced compared to young cells, allowing unfolded proteins to accumulate and form aggregates.^[48] Mitochondrial dysfunction, a hallmark of aging, further drives protein aggregation through heightened oxidative modifications. Mitochondria produce reactive oxygen species (ROS) as byproducts of respiration, and age-related impairments in mitochondrial function elevate ROS levels, leading to oxidative damage of proteins. This results in carbonylation and other modifications that alter protein structure, promoting insolubility and aggregation; for instance, oxidized protein levels increase by approximately 50-70% in aging brains.^[49] Such damage overwhelms the proteostasis network, as modified proteins resist degradation and sequester functional chaperones, creating a vicious cycle of aggregate formation. Additionally, proteasome activity, essential for clearing damaged proteins, declines substantially in aged rodents, with 26S proteasome function dropping by about 50% in the brains of old mice compared to young ones.^[50] This reduction links to the accumulation of indigestible aggregates like lipofuscin, a fluorescent pigment composed of 30-70% oxidized proteins and lipids that forms in lysosomes and inhibits further proteolysis, accelerating cellular senescence.^[51] From an evolutionary perspective, protein aggregation serves as a marker of senescence, reflecting trade-offs in proteostasis efficiency across species. Long-lived species invest more in protective mechanisms like chaperones and rapid protein turnover to minimize aggregation risk, but even they experience age-dependent declines. Proteins with high turnover rates exhibit greater intrinsic aggregation propensity yet are safeguarded by efficient degradation; however, aging impairs this balance, increasing aggregate burden as a senescence indicator.^[52] Longitudinal studies in model organisms underscore this correlation: in Caenorhabditis elegans, protein aggregation burden rises with age, involving over 460 proteins becoming insoluble, and directly inversely correlates with lifespan—mutations extending longevity, such as reduced insulin/IGF-1 signaling, delay aggregation and enhance survival.^[53] These findings highlight how chronic proteostasis erosion over time, distinct from acute stresses, culminates in widespread aggregation as a fundamental aging feature.

Cellular Localization

In Prokaryotic Cells

In prokaryotic cells, protein aggregates primarily form in the cytoplasm due to the absence of membrane-bound organelles, often resulting from environmental stresses or high-level expression of foreign proteins. These aggregates, known as inclusion bodies, are dense, amorphous structures composed of misfolded proteins that can impair cellular function if not managed. Prokaryotic aggregates, such as inclusion bodies, primarily form intracellularly in the cytoplasm, though some functional amyloids assemble extracellularly via dedicated secretion pathways. Cytoplasmic inclusion bodies in Escherichia coli exhibit polar localization, preferentially accumulating at the cell poles rather than dispersing evenly throughout the cytoplasm. This positioning arises from initial formation at discrete sites such as poles, mid-cell, or quarter-cell positions, with aggregates showing limited mobility (<10% relocation per division) and tending to segregate asymmetrically into daughter cells inheriting the old pole. In non-stressed conditions, this leads to higher aggregate density in aging cells at old poles, correlating with reduced reproductive fitness (>30% growth rate decline). During recombinant protein production, inclusion bodies are a common outcome when overexpressing heterologous proteins, as rapid synthesis overwhelms folding chaperones, leading to hydrophobic exposure and aggregation; however, they serve as a protective sink, enabling high yields (up to grams per liter) that can be solubilized post-purification for industrial applications like enzyme production.^[54]^[55] Polar foci of aggregates in bacteria like Salmonella and Shigella are driven by nucleoid exclusion, where the dense DNA nucleoid acts as a diffusion barrier, confining misfolded proteins and chaperone-substrate complexes to nucleoid-free polar regions. Under stress conditions such as heat or nutrient limitation, this mechanism seeds aggregate growth in polar zones, as seen with type III secretion substrates forming large dynamic complexes that reverse upon stress relief. Specific chaperones like IbpA and IbpB mark these sites in E. coli, with IbpA acting as a sequestrase to bind and hold aggregation-prone proteins, preventing further toxicity while facilitating later processing; IbpB complements by aiding substrate handover to disaggregases.^[56]^[57] Bacterial disaggregases, notably ClpB, enable aggregate reversibility by cooperating with the DnaK (Hsp70) system to solubilize and refold proteins during recovery phases. ClpB threads aggregate polypeptides through its central pore using ATP hydrolysis, initiated by DnaK coating the aggregate surface, which activates ClpB's ATPase and promotes partial unfolding for chaperone-mediated refolding rather than degradation. This dynamic process restores proteostasis post-stress, with ClpB essential for thermotolerance in bacteria like E. coli. In contrast to eukaryotic systems with compartmentalized clearance, prokaryotic aggregates rely on these cytoplasmic mechanisms for sequestration and dissolution.^[58]

In Eukaryotic Cells

In eukaryotic cells, protein aggregation exhibits organelle-specific patterns that reflect the compartmentalized nature of these organisms, differing from the more uniform cytoplasmic deposition observed in prokaryotes. Misfolded secretory proteins, which enter the secretory pathway, frequently aggregate within the endoplasmic reticulum (ER) and Golgi apparatus due to impaired folding or overload of the quality control machinery. In the ER, accumulation of unfolded or misfolded proteins triggers the unfolded protein response (UPR), but persistent stress leads to aggregation of these proteins, often forming insoluble deposits that disrupt ER homeostasis.^[45] Similarly, at the Golgi, post-ER quality control mechanisms retain unfolded proteins, preventing their trafficking; failure of this retention can result in aggregation within Golgi compartments, as seen in mammalian cells where misfolded glycoproteins accumulate and are targeted for degradation.^[59] These ER- and Golgi-associated aggregates highlight the secretory pathway's vulnerability to proteotoxic stress in fungi, plants, and animals. In the cytosol and nucleus, protein aggregates often manifest as ubiquitin-positive inclusions, serving as sites for sequestration of misfolded proteins. Cytosolic aggregates are frequently transported along microtubules to form aggresomes, perinuclear structures enriched in ubiquitin and molecular chaperones, which act as temporary storage for damaged proteins in mammalian cells and yeast.^[60] Nuclear aggregates, similarly ubiquitin-marked, arise from intranuclear misfolding events and can fuse to form larger inclusions, as observed in response to proteasomal inhibition across eukaryotic models.^[61] In yeast, specific cytosolic and nuclear sites include the insoluble protein deposit (IPOD), a peripheral aggregate lacking ubiquitin that recruits amyloid-like structures, and the juxtanuclear quality control (JUNQ) compartment, which is dynamic, proteasome-associated, and facilitates refolding or degradation of ubiquitinated proteins near the nucleus.^[62]^[63] Mitochondrial protein aggregation is prominently linked to oxidative damage, where reactive oxygen species (ROS) from electron transport chain dysfunction oxidize proteins, promoting their misfolding and intramitochondrial inclusion formation. In eukaryotes ranging from yeast to mammals, these aggregates sequester chaperones like Hsp60 and impair mitochondrial function, exacerbating proteotoxic stress under conditions such as aging or hypoxia.^[40] Distinct intramitochondrial aggregates, including spherical bodies and tubular structures, have been identified as protective mechanisms that isolate damaged proteins while preserving organelle integrity.^[64] In plants, vacuolar aggregates represent a key adaptation under abiotic stresses like drought, where water deficit induces protein misfolding and oxidative damage, leading to aggregate formation that is subsequently sequestered to the vacuole via autophagy for degradation. Autophagy adaptors such as NBR1 target ubiquitinated aggregates, including stress-responsive proteins like COST1, transporting them into autophagosomes that fuse with the vacuole, thereby enhancing drought tolerance by recycling nutrients and mitigating proteotoxicity.^[65]^[66] This vacuolar sequestration underscores the plant vacuole's role as a major protein quality control hub during environmental stress.

Aggregate Dynamics and Sequestration

Protein aggregates within cells exhibit dynamic behaviors that facilitate their transport, sequestration, and structural evolution, often serving as protective mechanisms against cytotoxicity. In eukaryotic cells, misfolded proteins forming small aggregates are actively transported along microtubules toward the microtubule-organizing center (MTOC) via dynein motors, leading to the consolidation into larger structures known as aggresomes.^[67] This dynein-mediated process is size-selective, with larger aggregates preferentially mobilized through episodic bursts of motility, enhancing their sequestration efficiency. In yeast, an actin-dependent mechanism complements this, where aggregates associate with Hsp104 and are retrogradely transported along actin cables to the mother cell, promoting asymmetric inheritance and clearance from daughter cells.^[68] Sequestration of aggregates often occurs in membrane-less compartments formed by liquid-liquid phase separation (LLPS), which temporarily isolate potentially harmful species. In Caenorhabditis elegans, P granules exemplify such sites, where RNA-binding proteins like LAF-1 drive LLPS to create dynamic droplets that sequester client proteins, including aggregates, while maintaining fluidity for selective partitioning during cell division.^[69] These phase-separated structures prevent widespread proteotoxicity by concentrating aggregates away from functional cellular regions, though prolonged residence can lead to further maturation.^[70] The structural dynamics of aggregates involve transitions from liquid-like to solid states, influencing their stability and propagation. Initially fluid condensates can undergo liquid-to-solid phase transitions, forming rigid amyloid fibrils that resist dissolution and serve as seeds for further aggregation.^[71] This maturation is evident in prion-like propagation, where fibrillar seeds template the misfolding of soluble monomers, enabling intercellular spread and amplification of aggregates in a self-perpetuating manner.^[72] Fluorescence recovery after photobleaching (FRAP) studies reveal that mature amyloid aggregates, such as those in plaques, possess immobile cores with minimal exchange, indicating a stable, non-dynamic architecture that perpetuates seeding.^[73] Additionally, aggregate stability is pH-sensitive; acidic environments can promote dissolution of certain amyloid assemblies, reversing fibril formation and highlighting environmental modulation of dynamics.^[73]

Clearance Mechanisms

Molecular Chaperone Refolding

Molecular chaperones play a crucial role in counteracting protein aggregation by actively refolding misfolded or aggregated polypeptides, thereby restoring functional conformations without degradation. These ATP-dependent machines recognize hydrophobic regions exposed in unfolded or aggregated states, preventing further assembly into insoluble aggregates. The process involves sequential binding, unfolding, and release cycles that solubilize proteins, particularly under cellular stress conditions where aggregation propensity increases.^[74] The Hsp70 chaperone system exemplifies this refolding mechanism, utilizing ATP hydrolysis to thread substrates through its central cavity in an iterative manner. Hsp70 binds to exposed hydrophobic segments of aggregated proteins, facilitated by collaboration with Hsp40 co-chaperones, which deliver substrates and stimulate ATP hydrolysis to lock Hsp70 in a high-affinity state. This threading action extracts polypeptides from aggregates, allowing subsequent refolding upon release by nucleotide exchange factors. Cryo-EM structures from the 2010s have illuminated this model, revealing how Hsp70's ATPase domain powers conformational changes that pull substrates unidirectionally through the pore. However, under conditions of severe aggregate overload, such as prolonged heat stress, the system's efficiency diminishes as chaperone capacity is saturated, leading to incomplete disaggregation.^[75]^[76]^[77] In prokaryotes and yeast, specialized disaggregases like bacterial ClpB and yeast Hsp104 enhance Hsp70's capabilities as hexameric AAA+ ATPases that actively pull polypeptides from aggregates. These ring-shaped enzymes form central pores through which substrates are threaded in an ATP-fueled process, uncoiling even tightly packed structures like amyloid fibrils. ClpB relies on DnaK (the bacterial Hsp70 homolog) for targeting, while Hsp104 integrates with Ssa1, ensuring coordinated disaggregation. Structural insights from cryo-EM confirm a conserved threading mechanism across these homologs, where ATP binding and hydrolysis drive subunit rotations that grip and translocate chains.^[78]^[79]^[80] Complementing these systems, small heat shock proteins (sHSPs) function as ATP-independent holdases that bind to aggregation-prone intermediates, stabilizing them in a soluble state to avert further clumping. By sequestering hydrophobic surfaces, sHSPs like alphaB-crystallin prevent irreversible aggregation during acute stress, later handing off clients to ATP-dependent chaperones for refolding. This holdase activity is vital in the initial triage of misfolded proteins, maintaining proteostasis until disaggregases can intervene.^[81]^[82]

Proteasomal and Lysosomal Degradation

Protein aggregation poses a challenge to cellular proteostasis, and cells employ the ubiquitin-proteasome system (UPS) to degrade misfolded or aggregated proteins that cannot be refolded by chaperones. The UPS begins with the covalent attachment of ubiquitin to target proteins through a hierarchical enzymatic cascade involving E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. E1 enzymes activate ubiquitin by forming a thioester bond using ATP, which is then transferred to E2 enzymes; subsequently, E3 ligases facilitate the transfer of ubiquitin to lysine residues on the substrate protein, often recognizing specific degradation signals.^[83] This process typically requires the formation of polyubiquitin chains, where the type of linkage determines the fate of the modified protein: K48-linked chains signal for proteasomal degradation, while K63-linked chains primarily mediate non-degradative functions such as signaling or trafficking.^[84] The 26S proteasome, a large ATP-dependent complex approximately 2.5 MDa in size, executes the degradation of ubiquitinated proteins. It consists of a 20S core particle with proteolytic activity and two 19S regulatory particles that recognize and prepare substrates. The 20S core features three main catalytic activities, including chymotrypsin-like activity at the β5 subunit, which cleaves peptide bonds after large hydrophobic residues to generate peptides from unfolded proteins. The 19S regulatory particle's Rpt ATPase subunits unfold substrates and open the gate of the 20S core, ensuring selective entry and preventing unregulated proteolysis.^[85] In parallel, lysosomal degradation handles extracellular or membrane-associated aggregates through endocytosis, where cells internalize protein aggregates via receptor-mediated or fluid-phase pathways, delivering them to lysosomes for hydrolysis. Within the acidic lysosomal lumen (pH ~4.5-5.0), cathepsin proteases, such as cathepsin B and D, perform the bulk degradation by cleaving proteins into amino acids, with cathepsins exhibiting optimal activity in this low-pH environment.^[86]^[87] Unlike the UPS, which targets soluble or small oligomeric aggregates, lysosomal pathways are more suited for larger extracellular complexes, though both systems can intersect with chaperone-assisted delivery for efficient clearance.^[86] Recent studies have identified a cell cycle stage-dependent mechanism for clearing protein aggregates during mitosis in human cells, involving the ER chaperone BiP, proteasome activity, and inactivation of cyclin-dependent kinase (CDK), which facilitates the dissolution and degradation of ER-associated aggregates.^[88] Age-related decline in proteasomal function exacerbates protein aggregation, as oxidative damage and reduced expression of catalytic subunits lead to inhibited activity and accumulation of ubiquitinated substrates. In yeast, the insoluble protein deposit (IPOD), a perivacuolar structure, sequesters non-ubiquitinated aggregates, which under stress conditions can be delivered to the vacuole for degradation.^[89]^[62]

Autophagy Pathways

Autophagy represents a critical cellular mechanism for the degradation of large protein aggregates that exceed the capacity of proteasomal pathways, particularly through macroautophagy, where double-membrane vesicles known as autophagosomes engulf cytoplasmic cargo for delivery to lysosomes. In the context of protein aggregation, selective forms of autophagy, such as aggrephagy, target ubiquitinated protein aggregates for specific recognition and clearance. Aggrephagy relies on adaptor proteins like p62/SQSTM1, which bind to ubiquitin chains on aggregates via its ubiquitin-associated domain and simultaneously interact with lipidated LC3 on autophagosomal membranes through its LC3-interaction region, thereby linking aggregates to the autophagic machinery.^[90]^[91] The formation of autophagosomes is orchestrated by autophagy-related (Atg) proteins, which coordinate membrane nucleation, elongation, and closure; core components include the Atg1/ULK complex for initiation, the phosphatidylinositol 3-kinase complex for phospholipid production, and the Atg12 and LC3 conjugation systems for membrane expansion. A hallmark of this process is the lipidation of LC3 to form LC3-II, where LC3 is conjugated to phosphatidylethanolamine on the autophagosomal membrane, serving as a key marker for autophagosome maturation and cargo recruitment.^[92]^[93] Once formed, autophagosomes fuse with lysosomes to form autolysosomes, where degradation occurs; this fusion is mediated by SNARE proteins, including syntaxin 17 (STX17) on the autophagosome, SNAP29, and VAMP7 or VAMP8 on the lysosome, facilitated by tethering complexes like HOPS.^[94]^[95] Beyond aggrephagy, mitophagy selectively degrades mitochondria containing aggregated or damaged proteins, often triggered by PINK1-Parkin ubiquitination pathways that recruit autophagy receptors to damaged organelles, thereby preventing the release of toxic aggregates from mitochondria. Chaperone-mediated autophagy (CMA), while primarily targeting soluble proteins bearing KFERQ-like motifs via HSC70 chaperone recognition and LAMP2A translocation to lysosomes, can indirectly influence aggregation by clearing monomeric precursors before they form insoluble aggregates.^[96] In models of neurodegeneration, such as those involving Huntington's or Parkinson's diseases, autophagy pathways, including aggrephagy and mitophagy, are often upregulated as a compensatory response to protein aggregate accumulation, with enhanced LC3-II levels and Atg protein expression observed in affected neurons to mitigate proteotoxicity.^[97]

Pathological Consequences

Mechanisms of Toxicity

Protein aggregates exert toxicity through gain-of-function mechanisms, where soluble oligomers interact directly with cellular components to disrupt normal function. These oligomers, often prefibrillar species, can insert into lipid bilayers to form pore-like structures, such as β-barrel channels, leading to membrane permeabilization and uncontrolled ion fluxes. This disruption compromises plasma and organelle membranes, particularly in mitochondria, causing leakage of cellular contents and impairment of bioenergetic processes. A key consequence is the dysregulation of calcium homeostasis, as oligomers facilitate calcium influx, which triggers downstream signaling cascades including excitotoxicity and activation of proteases like calpains.^[98]^[99]^[100] Beyond direct membrane interactions, protein aggregates induce toxicity by sequestering essential components of the proteostasis network, overwhelming cellular quality control systems. Misfolded proteins and aggregates bind to molecular chaperones such as Hsp70 and Hsp90, titrating them away from their normal substrates and impairing the refolding of nascent or stressed proteins. Similarly, aggregates can clog the proteasome by forming insoluble inclusions that inhibit ubiquitin-dependent degradation, leading to backlog of ubiquitinated proteins. This overload culminates in a collapse of global proteostasis, where the cell's capacity to maintain protein homeostasis is eroded, exacerbating misfolding of unrelated proteins and amplifying aggregate formation.^[101]^[102]^[103] Aggregates also trigger inflammatory responses by activating innate immune pathways, notably through the NLRP3 inflammasome. Fibrillar aggregates, such as those from amyloidogenic proteins, serve as danger signals that prime and assemble the NLRP3-ASC-caspase-1 complex in immune cells like microglia and macrophages. This activation processes pro-IL-1β and pro-IL-18 into mature cytokines, promoting a proinflammatory milieu that amplifies tissue damage via recruitment of additional immune cells and release of reactive mediators.^[104]^[105] At the synaptic level, certain oligomers exemplify neurotoxic gain-of-function by interfering with plasticity mechanisms; for instance, amyloid-β (Aβ) oligomers bind to receptors like NMDA and AMPA, suppressing long-term potentiation (LTP) through oxidative modulation of synaptic proteins and disruption of glutamate signaling. This selective impairment of LTP, without affecting basal transmission, underscores how oligomers target vulnerable neuronal compartments to erode memory-related circuits.^[106]^[107] Toxicity is further propagated through seeding mechanisms, where aggregates act as templates to recruit and convert soluble monomers into misfolded conformers, facilitating intercellular spread. In transmissible aggregates akin to prions, this templated misfolding enables cell-to-cell propagation via exosomes, tunneling nanotubes, or direct uptake, perpetuating a cycle of aggregation across tissues.^[108]^[109] Finally, aggregates contribute to oxidative stress by catalyzing reactive oxygen species (ROS) generation, often through Fenton-like chemistry involving bound transition metals like iron or copper. Oligomers and fibrils coordinate these metals at their hydrophobic cores, enabling the reduction of H₂O₂ to hydroxyl radicals (•OH), which damage lipids, nucleic acids, and proteins in a vicious cycle that promotes further aggregation.^[110]^[40]^[111]

Associated Diseases and Disorders

Protein aggregation is a central pathological feature in numerous human diseases, particularly those involving the accumulation of misfolded proteins into amyloid fibrils or inclusion bodies, leading to cellular dysfunction and tissue damage. In neurodegenerative disorders, intracellular and extracellular aggregates disrupt neuronal function, while in systemic conditions, they affect multiple organs. These pathologies often share mechanisms such as prion-like propagation of aggregates, though disease-specific proteins and triggers vary.^[112] Alzheimer's disease (AD) is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, both resulting from aberrant protein aggregation. Less than 5% of AD cases are early-onset familial forms linked to mutations in genes like APP, PSEN1, and PSEN2 that accelerate Aβ production and aggregation. Positron emission tomography (PET) imaging with amyloid-specific tracers, such as florbetapir, enables noninvasive detection of Aβ plaques, aiding early diagnosis and differentiation from other dementias.^[113]^[114]^[115] In Parkinson's disease (PD), aggregation of α-synuclein into Lewy bodies within neurons of the substantia nigra contributes to dopaminergic neuron loss and motor symptoms. These intraneuronal inclusions are a hallmark of both sporadic and familial PD, with mutations in SNCA or LRRK2 promoting α-synuclein misfolding and fibrillization.^[112] Amyotrophic lateral sclerosis (ALS) involves the aggregation of superoxide dismutase 1 (SOD1) in motor neurons, forming cytoplasmic inclusions that impair axonal transport and lead to progressive paralysis. Familial ALS cases, accounting for about 10% of all ALS, often feature SOD1 mutations that destabilize the protein and enhance its propensity to aggregate.^[112] Systemic diseases also feature protein aggregation, as seen in type 2 diabetes mellitus (T2DM), where islet amyloid polypeptide (IAPP) aggregates into amyloid deposits in pancreatic β-cells, contributing to β-cell apoptosis and insulin deficiency. These extracellular IAPP amyloids are present in up to 90% of T2DM pancreata at autopsy. Similarly, cardiac amyloidosis arises from transthyretin (TTR) protein misfolding and aggregation into fibrils that infiltrate the myocardium, causing restrictive cardiomyopathy; wild-type TTR aggregates in senile systemic amyloidosis, while mutant forms drive hereditary variants.^[116] Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are caused by the conformational conversion of cellular prion protein (PrPC) into the pathogenic scrapie isoform (PrPSc), which self-propagates through templated misfolding and forms extracellular amyloid plaques in the brain, leading to spongiform encephalopathy. Sporadic CJD, the most common form, accounts for about 85% of human prion diseases and involves de novo PrPSc generation without identifiable external exposure.^[117] Extracellular aggregates also occur in AA amyloidosis, a secondary form triggered by chronic inflammation from conditions like rheumatoid arthritis or infections, where serum amyloid A protein (SAA) deposits as fibrils primarily in kidneys and other organs, leading to organ failure. This reactive amyloidosis highlights how sustained inflammatory responses can drive systemic protein aggregation independently of genetic factors.^[118]

Biotechnological and Therapeutic Aspects

Challenges in Biomanufacturing

In recombinant protein production using Escherichia coli as a host, protein aggregation into inclusion bodies (IBs) represents a major obstacle, often leading to reduced yields and complicating downstream processing. IBs form when overexpressed heterologous proteins misfold and aggregate, resulting in insoluble particles that can constitute up to 30-50% of total cellular protein, thereby lowering the recoverable soluble fraction and necessitating additional solubilization and refolding steps. These refolding protocols, which typically involve denaturants like urea or guanidine hydrochloride followed by controlled renaturation, are labor-intensive and can achieve recovery rates as low as 20-50% for some proteins, further impacting overall process efficiency.^[55]^[119]^[120] During purification, protein stability is frequently compromised by mechanical and chemical stresses, such as shear forces from pumping or mixing and pH shifts in chromatography steps, which expose hydrophobic regions and promote aggregation. High shear rates, often exceeding 10^4 s^-1 in industrial-scale operations, can induce partial unfolding, particularly in viscous solutions, leading to dimer and higher-order aggregate formation at rates that correlate with exposure duration. Similarly, pH excursions below 4 or above 8 during ion-exchange or viral inactivation can alter electrostatic interactions, destabilizing proteins and increasing aggregate content by 5-20% in susceptible cases like monoclonal antibodies (mAbs).^[121]^[122]^[123] In mAb biomanufacturing, aggregation contributes to substantial production losses, with aggregate levels during cell culture reaching up to 30% in some processes, necessitating removal steps that can reduce overall yields by 20-50%. Regulatory guidelines emphasize minimizing aggregates due to immunogenicity risks, with acceptable levels of soluble aggregates typically limited to below 5-10% in injectable formulations to ensure product safety and efficacy. To mitigate interface-induced aggregation during formulation and storage, non-ionic surfactants such as polysorbate 20 or 80 are commonly added at concentrations of 0.01-0.1% (w/v), where they compete for adsorption at air-liquid or solid-liquid interfaces, reducing protein exposure and aggregate formation by up to 90% in stressed conditions.^[124]^[125]^[126]

Strategies for Prevention and Treatment

Strategies for preventing and treating protein aggregation primarily involve pharmacological interventions that stabilize proteins, inhibit nucleation and elongation steps in the aggregation pathway, or enhance clearance mechanisms, alongside genetic approaches targeting underlying mutations. Small-molecule stabilizers, such as tafamidis, bind to transthyretin (TTR) to prevent its dissociation into monomers that initiate amyloid formation, thereby reducing all-cause mortality and cardiovascular hospitalizations in patients with TTR amyloid cardiomyopathy (ATTR-CM). In the phase 3 ATTR-ACT trial, tafamidis treatment resulted in a 30% reduction in mortality risk over 30 months compared to placebo.^[127] Kinetic inhibitors target the early nucleation phase of aggregation, where monomers form critical oligomers, by altering the thermodynamic and kinetic barriers to fibril formation; for instance, compounds designed to bind transiently to aggregation-prone intermediates can extend the lag phase of amyloid assembly by orders of magnitude in vitro.^[128] Gene therapies, particularly antisense oligonucleotides (ASOs), offer targeted silencing of mutant alleles prone to aggregation. Tofersen, an ASO approved for SOD1-mutated amyotrophic lateral sclerosis (ALS), binds SOD1 mRNA to reduce SOD1 protein levels by 33% (95% CI -47 to -16%) in cerebrospinal fluid, slowing disease progression as evidenced by decreased neurofilament light chain levels in phase 1-2 trials.^[129] Chaperone inducers like arimoclomol amplify the heat shock protein (HSP) response under stress, enhancing protein refolding and inhibiting aggregation in neurodegenerative contexts; in the phase 2/3 trial for rapidly progressive SOD1-ALS, arimoclomol treatment was associated with a slower decline of 0.5 points per month on the ALSFRS-R scale compared to placebo (95% CI -0.63 to 1.63) over up to 12 months.^[130] Antibody-based therapies promote clearance of extracellular aggregates, such as amyloid-beta (Aβ) plaques in Alzheimer's disease. Lecanemab, a monoclonal antibody targeting protofibrils, reduces Aβ deposition and slows cognitive decline by 27% on the CDR-SB scale in early-stage patients over 18 months, as shown in the phase 3 Clarity AD trial.^[131] In type 2 diabetes, where islet amyloid polypeptide (IAPP) aggregation contributes to beta-cell dysfunction, glucagon-like peptide-1 receptor agonists like semaglutide have demonstrated preclinical efficacy in reducing IAPP accumulation by improving extracellular matrix remodeling and proteoglycan turnover in obese mouse models.^[132] For biotechnological applications, directed evolution techniques engineer aggregation-resistant protein variants by iteratively mutating and selecting for improved solubility and stability during biomanufacturing. An in vivo selection platform using bacterial growth assays has successfully evolved single-chain variable fragments (scFvs) with enhanced resistance to thermal aggregation, yielding variants that maintain functionality when reformatted as full immunoglobulins for therapeutic production.^[133] These approaches collectively address aggregation in both therapeutic and industrial settings by prioritizing interventions that modulate kinetics or genetics without relying solely on downstream clearance.

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The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines.
[103]
Soluble Oligomers of the Amyloid β-Protein Impair Synaptic ...
We find that these naturally secreted soluble oligomers -- at picomolar concentrations -- can disrupt hippocampal LTP in slices and in vivo and can also impair ...
[104]
Soluble Aβ Oligomers Inhibit Long-Term Potentiation through a ...
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[105]
Prion-like transmission of protein aggregates in neurodegenerative ...
Recent studies suggest that these aggregates are capable of crossing cellular membranes and can directly contribute to the propagation of neurodegenerative ...
[106]
Cellular mechanisms of protein aggregate propagation - PMC
Seeded aggregation is the process by which protein aggregates induce misfolding of the cognate monomer in vitro. Transcellular propagation is the process by ...
[107]
Protein aggregation, metals and oxidative stress in ... - Portland Press
Oct 26, 2005 · Our recent results suggest that ROS are generated during the very early stages of protein aggregation, when protofibrils or soluble oligomers ...
[108]
Protein aggregation as a cellular response to oxidative ... - PNAS
Nov 7, 2016 · The labile Fe can catalyze the generation of ROS via a Fenton reaction (7). Given our results showing that the formation of ALIS induced by ...
[109]
Protein aggregation and neurodegenerative disease - Nature
Jul 1, 2004 · Covalent modifications of proteins may facilitate aggregation. Sporadic neurodegenerative diseases are generally associated with aging, which ...
[110]
New Insights into the Molecular Bases of Familial Alzheimer's Disease
Apr 19, 2020 · In particular, it has been estimated that 15–25% of total AD accounts for familial Alzheimer's disease (FAD) (Figure 1) [5]. Figure 1. Figure 1.
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The Role of Amyloid PET in Imaging Neurodegenerative Disorders
Amyloid PET is a crucial tool for the diagnosis of Alzheimer disease, as it allows the noninvasive detection of amyloid plaques.
[112]
Type 2 Diabetes as a Protein Misfolding Disease - PubMed Central
Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to β-cell dysfunction and disease.
[113]
Cellular and Molecular Mechanisms of Prion Disease - PMC
Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely ...
[114]
AA Amyloidosis: A Contemporary View - PMC - PubMed Central
Apr 3, 2024 · Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of chronic inflammatory disorders. Here, we review the epidemiology, ...
[115]
Protein recovery from inclusion bodies of Escherichia coli using mild ...
Mar 25, 2015 · Inclusion body aggregates are of highly dynamic nature. Besides the recombinant protein, inclusion bodies also contain components from bacterial ...
[116]
Advances in Escherichia coli-Based Therapeutic Protein Expression
Proteins overexpressed in E. coli may form insoluble aggregates known as inclusion bodies, requiring specific solubilization and refolding steps, adding ...5. Bioinformatics... · 6. Gene Cloning And Design · 6.1. Ribosomes
[117]
Shear stress as a driver of degradation for protein-based therapeutics
Jan 25, 2024 · A product may be sensitive to numerous stability stressors, such as temperature, pH or ionic strength changes, oxidation, light exposure, ...
[118]
Impact of Cavitation, High Shear Stress and Air/Liquid Interfaces on ...
Mar 25, 2018 · The reported impact of shear stress on protein aggregation has been contradictory. At high shear rates, the occurrence of cavitation or ...
[119]
Stabilization challenges and aggregation in protein-based ... - NIH
Dec 11, 2023 · Alterations in pH can disturb the charge balance within the protein resulting in modifications of its conformation and stability. Additionally, ...
[120]
Aggregates in Monoclonal Antibody Manufacturing Processes
In this review it is analyzed how aggregates are formed during monoclonal antibody industrial production, why they have to be removed and the manufacturing ...
[121]
Protein Aggregation and Immunogenicity of Biotherapeutics - PMC
A small amount of soluble aggregates, between 5 to 10%, for example, may be acceptable in biologic products, because the belief is that it is generally ...
[122]
Exploring the Protein Stabilizing Capability of Surfactants Against ...
The application of surfactants in liquid protein formulation is a common practice to protect proteins from liquid-air interface-induced protein aggregation.
[123]
Tafamidis Treatment for Patients with Transthyretin Amyloid ...
Sep 13, 2018 · Methods: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin ...
[124]
Thermodynamic and kinetic design principles for amyloid ... - PNAS
We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures ...
[125]
Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Jul 8, 2020 · Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis.
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Efficacy of Arimoclomol for Amyotrophic Lateral Sclerosis
Apr 7, 2025 · The results show that arimoclomol was associated with a slightly slower decline in ALSFRS-R scores compared to placebo, with a mean difference of 2.64.
[127]
Lecanemab in Early Alzheimer's Disease
Nov 29, 2022 · Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at ...
[128]
Treatment with semaglutide, a GLP-1 receptor agonist, improves ...
Apr 15, 2023 · Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM.Missing: clinical trial
[129]
An in vivo platform to select and evolve aggregation-resistant proteins
Apr 14, 2020 · Using this assay as a directed evolution screen, we demonstrate the generation of aggregation resistant scFv sequences when reformatted as IgGs.Results · Protein Aggregation... · MethodsMissing: biomanufacturing | Show results with:biomanufacturing