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Huntingtin

Huntingtin is a large, 350 kDa protein encoded by the HTT gene located on the short arm of human chromosome 4 at position 4p16.3, and it is highly conserved across vertebrate species.^[1] This protein plays essential roles in multiple cellular processes, including axonal trafficking of vesicles and proteins such as brain-derived neurotrophic factor (BDNF), transcriptional regulation through interactions with factors like REST/NRSF and CREB-binding protein (CBP), and promotion of cell survival by inhibiting apoptosis pathways like caspase-3 activation.^[1] Mutations in the HTT gene, characterized by an expanded CAG trinucleotide repeat in the first exon that results in a polyglutamine (polyQ) tract longer than 36 residues (compared to the normal 6–35 repeats), lead to Huntington's disease (HD), an autosomal dominant neurodegenerative disorder primarily affecting striatal neurons in the brain.^[1] Structurally, huntingtin adopts an elongated, largely α-helical conformation forming a superhelical solenoid composed of multiple HEAT (huntingtin, elongation factor 3, A subunit of PP2A, and TOR1) repeats that facilitate protein-protein interactions, featuring a polyQ region and polyproline (polyP) tract near the N-terminus, followed by a central solenoid organized into N-terminal, bridge, and C-terminal domains.^[2] The protein also features post-translational modification sites for ubiquitination, sumoylation, phosphorylation, and palmitoylation, as well as a nuclear export signal, which regulate its localization and activity between cytoplasmic and nuclear compartments.^[1] In its normal state, huntingtin supports neuronal development and maintenance by coordinating intracellular transport along microtubules, modulating gene expression, and participating in endosomal-lysosomal pathways and autophagy.^[1] However, in HD, the expanded polyQ tract confers a toxic gain-of-function, promoting misfolding, aggregation into intranuclear inclusions, and disruption of cellular homeostasis, alongside partial loss-of-function that impairs wild-type activities like BDNF transport and transcription.^[1] Research into huntingtin's mechanisms has highlighted its interactions with partners like huntingtin-associated protein 40 (HAP40), which stabilizes its structure, and has informed therapeutic strategies targeting mutant protein clearance or repeat expansion correction.^[3] Recent studies, including cryo-electron tomography in 2025, have further revealed its interaction with F-actin filaments, highlighting roles in cytoskeletal organization.^[4] Despite advances in cryo-electron microscopy revealing its domain organization, the full spectrum of its physiological roles remains under investigation, with ongoing studies emphasizing its scaffolding function in diverse tissues beyond the brain.^[2]

Genetics

Gene Location and Organization

The HTT gene, encoding the huntingtin protein, is situated on the short arm of chromosome 4 at the 4p16.3 cytogenetic band in humans, with genomic coordinates spanning from 3,074,681 to 3,243,960 on the GRCh38 reference assembly.^[5] This locus encompasses approximately 169 kb of DNA and is organized into 67 exons, ranging in size from 48 to 341 base pairs with an average of 138 bp, interspersed by 66 introns that facilitate alternative splicing patterns.^[6] The promoter region of the HTT gene, located upstream of the transcription start site, is characterized by high GC content and the absence of TATA or CCAAT boxes, aligning with features of constitutively expressed genes. A key conserved regulatory element, showing 78.8% sequence identity between human and mouse homologs from positions -206 to -56, supports basal transcription, while binding sites for factors such as Sp1 (e.g., at -15 to -9) and HDBP1/2 (within -221 to -175) act as positive regulators. Additional elements, including 20-bp direct repeats (-213 to -174) and Alu sequences, further influence promoter activity and transcriptional initiation.^[7] Evolutionarily, the HTT gene exhibits remarkable conservation across chordates, preserving its 67-exon architecture and overall structure in vertebrates from mammals to fish. Orthologs include the Hdh gene in mice (Mus musculus), which shares 67 exons and high sequence similarity, and the htt gene in zebrafish (Danio rerio), featuring 67 exons with 18% amino acid divergence from other teleosts yet retaining essential functional domains. This conservation underscores the gene's critical role in development and cellular processes across species.^[8] The HTT gene displays ubiquitous expression in human tissues, consistent with its housekeeping-like function, though transcript and protein levels are notably highest in the brain and testes. Within the brain, expression predominates in neurons, while the two major transcripts (13.7 kb and 10.3 kb) vary by tissue, with the longer isoform enriched in neural contexts.^[1]^[5]

Mutations and Polymorphisms

The huntingtin gene (HTT) contains a polymorphic CAG trinucleotide repeat in its first exon, which is the primary site of pathogenic mutations associated with Huntington's disease. Normal alleles typically carry 6 to 35 CAG repeats, while alleles with 27 to 35 repeats are classified as intermediate; these do not cause disease in the carrier but carry a risk of expansion to pathogenic lengths during transmission to offspring. Pathogenic alleles have more than 36 CAG repeats, with expansions observed up to approximately 250 repeats in affected individuals, though lengths above 60 are rare and correlate with juvenile-onset disease.^[9]^[10]^[11] Huntington's disease caused by HTT CAG expansions follows an autosomal dominant inheritance pattern, requiring only one expanded allele for disease manifestation. A key feature is genetic anticipation, where successive generations experience earlier disease onset and increased severity due to further expansion of the CAG repeat, particularly during paternal meiosis when instability is more pronounced. This instability also leads to somatic mosaicism, with varying repeat lengths observed across different tissues in individuals with expanded alleles, contributing to heterogeneous disease progression.^[9]^[12] Beyond CAG repeat expansions, the HTT locus harbors various single nucleotide polymorphisms (SNPs) that exert minor modulatory effects on disease penetrance and age of onset. For instance, the SNP rs13102260 (G>A) in the HTT promoter disrupts NF-κB binding, reducing HTT transcription and acting as a bidirectional modifier: it delays onset in mutant allele carriers while potentially exacerbating symptoms when on the normal allele. Other SNPs, such as those influencing DNA repair pathways or cis-regulatory elements, have been implicated in fine-tuning penetrance, though their impact is overshadowed by CAG repeat length.^[13] Diagnosis of HTT-related mutations relies on genetic testing to determine CAG repeat length, with polymerase chain reaction (PCR) serving as the primary method for alleles up to about 115 repeats due to its sensitivity and specificity. For larger expansions that may exceed PCR's reliable detection range, Southern blot analysis is employed to visualize the full repeat tract size, often in combination with triplet-primed PCR for confirmation. These criteria enable predictive testing in at-risk individuals and presymptomatic diagnosis, following established guidelines to ensure accurate categorization of normal, intermediate, and pathogenic alleles.^[9]^[10]^[11]

Protein Structure

Primary Sequence and Domains

The human huntingtin (HTT) protein is a large polypeptide consisting of 3,142 amino acids with a predicted molecular mass of approximately 350 kDa, encoded by the HTT gene on chromosome 4.^[14] The primary sequence begins with an N-terminal region featuring a short 17-amino-acid segment (N17 domain, residues 1-17), immediately followed by a polyglutamine (polyQ) tract (residues 18 onward, typically 6-35 glutamines in wild-type) and a subsequent proline-rich region (PRR, residues approximately 51-97).^[15] These N-terminal elements contribute to the protein's modular organization, with the polyQ tract arising from CAG trinucleotide repeats in the gene.^[16] The core of the HTT protein is characterized by an extensive array of HEAT repeats, predicted to form 21 alpha-helical segments that assemble into a solenoid-like scaffold structure spanning much of the central and C-terminal regions (approximately residues 100-2,500).^[17] This HEAT-rich domain lacks any enzymatic active sites, underscoring HTT's role as a non-catalytic scaffolding protein that facilitates interactions with other cellular components.^[16] Recent structural studies using cryo-electron microscopy have further revealed that huntingtin forms complexes with F-actin, cross-linking actin filaments to support cytoskeletal organization and axonal growth.^[4] The N17 domain is implicated in subcellular localization, while the overall alpha-helical architecture provides flexibility and binding surfaces essential for structural integrity.^[18] Toward the C-terminus (residues beyond approximately 2,500), HTT contains motifs that mediate nucleocytoplasmic shuttling, including a highly conserved nuclear export signal (NES, residues 2,414-2,430) recognized by the CRM1/exportin pathway and nuclear import signals that enable translocation via importin pathways.^[19] These features allow bidirectional movement across the nuclear envelope, with the absence of dedicated enzymatic domains further emphasizing the protein's reliance on structural modularity for function.^[1] Sequence conservation across species highlights HTT's evolutionary importance, though length varies; for instance, the Drosophila melanogaster ortholog is longer at 3,583 amino acids, while the Caenorhabditis elegans homolog is more compact at around 1,000 residues, yet the HEAT repeats remain largely preserved in number and arrangement.^[8] In vertebrates like mice, the protein mirrors the human length at 3,142 amino acids, maintaining high sequence identity (>95%) in the HEAT domains.^[20]

Post-Translational Modifications

Huntingtin undergoes a variety of post-translational modifications that fine-tune its stability, subcellular localization, and activity, including phosphorylation, SUMOylation, ubiquitination, acetylation, palmitoylation, and proteolytic cleavage by caspases. These modifications occur at specific residues and are mediated by dedicated enzymes, influencing the protein's interactions with cellular compartments and pathways for degradation. For instance, phosphorylation and SUMOylation primarily affect nuclear and cytoplasmic distribution, while lipid modifications like palmitoylation promote membrane association.^[21] Phosphorylation targets several serine residues within huntingtin, with key sites including Ser13, Ser16, and Ser421. Phosphorylation at Ser421 is catalyzed by Akt (protein kinase B) or serum- and glucocorticoid-induced kinase (SGK), which stabilizes the protein by inhibiting its cleavage and facilitates vesicular transport of brain-derived neurotrophic factor (BDNF).^[22]^[23] In contrast, phosphorylation at Ser13 and Ser16 by IκB kinase (IKK) enhances proteasomal degradation and reduces the protein's aggregation propensity.^[24] These site-specific phosphorylations generally decrease the tendency for polyglutamine tract aggregation, thereby modulating overall protein solubility and function.^[24] SUMOylation modifies huntingtin at lysine residues Lys6 and Lys9, primarily through the action of the E3 ligase Ras homolog enriched in striatum (Rhes) or other SUMO machinery. This modification promotes nuclear retention of the protein and stabilizes it against degradation, altering its localization and potential for aggregation.^[25]^[26] SUMOylation at these sites competes with other modifications, influencing the balance between nuclear accumulation and clearance.^[27] Ubiquitination and acetylation serve as signals for protein degradation. Ubiquitination occurs at Lys6, Lys9, and Lys15, mediated by E2-conjugating enzymes like E2-25K or E3 ligases such as CHIP, directing huntingtin to the ubiquitin-proteasome system for breakdown and thereby regulating its steady-state levels.^[28]^[29] Acetylation at Lys444 by the histone acetyltransferase CREB-binding protein (CBP) targets the protein to autophagosomes, facilitating lysosomal degradation and maintaining cellular homeostasis.^[30] Palmitoylation, a reversible lipid modification, attaches palmitate to cysteine residues such as Cys105, Cys214, Cys433, Cys3134, and Cys3144, catalyzed by palmitoyl acyltransferases ZDHHC17 (also known as HIP14) and ZDHHC13 (HIP14L). This modification increases the protein's hydrophobicity, enabling association with cellular membranes and lipid rafts, which supports its roles in trafficking and synaptic function while reducing aggregation.^[31]^[32] Proteolytic cleavage by caspases generates truncated fragments of huntingtin, with a prominent site at Asp552 cleaved by caspase-6 (and to a lesser extent caspase-3). This processing produces N-terminal fragments that exhibit altered localization and increased propensity for aggregation, impacting protein turnover. Such cleavage events are part of normal regulatory mechanisms but can influence the generation of bioactive peptides.^[33]

Normal Functions

Intracellular Trafficking

Huntingtin (HTT) plays a critical role in axonal transport by interacting with microtubule-based motor proteins, including kinesin-1 and dynein/dynactin complexes, to facilitate the movement of vesicles along axons. These interactions enable the efficient delivery of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which are essential for neuronal survival and function. Phosphorylation of HTT at serine 421 acts as a molecular switch, enhancing its binding to these motors and promoting bidirectional transport of vesicles, thereby coordinating anterograde and retrograde movements. Structural features of HTT, particularly its N-terminal domain and interactions mediated by HAP1, enable these motor associations, allowing HTT to serve as a scaffold for motor coordination.^[34]^[35]^[36] In endocytosis, HTT regulates vesicle formation and trafficking through associations with huntingtin-associated protein 1 (HAP1) and clathrin, components of clathrin-coated pits. HAP1 mediates HTT's recruitment to endocytic sites, influencing the internalization of receptors and ligands at the plasma membrane. Beyond endocytosis, HTT contributes to the secretory pathway by supporting ER-to-Golgi transport and exocytosis; it associates with exocytic vesicles in adrenal chromaffin cells, where HAP1 aids in vesicle docking and rapid release of contents, such as catecholamines. These roles ensure proper membrane trafficking in both endocytic and secretory routes. HTT also plays essential roles in vesicular transport during early embryonic development and in non-neuronal tissues, contributing to overall cellular organization.^[1]^[37]^[38]^[39] HTT promotes autophagy by functioning as a scaffold for selective macroautophagy, aiding in cargo recognition and delivery to lysosomes. It interacts with autophagy adaptors like HAP1 and p62 to facilitate the engulfment and transport of ubiquitinated cargoes, including damaged organelles. In mitophagy, a form of selective autophagy, HTT supports the lysosomal targeting of mitochondria via its ubiquitin-binding domain, ensuring clearance of impaired mitochondria. HTT's involvement in autophagosome dynamics further enhances fusion with lysosomes, maintaining cellular homeostasis.^[40]^[41]^[42] Evidence from genetic models underscores HTT's essentiality in trafficking; complete knockout of HTT in mice results in embryonic lethality around E7.5-E8.5, attributed to severe disruptions in vesicular transport and early embryonic development. Conditional neuronal knockouts reveal progressive defects in axonal trafficking, confirming HTT's indispensable role in intracellular logistics without which cellular organization fails.^[43]^[35]^[44]

Gene Expression Regulation

Huntingtin plays a critical role in transcriptional co-activation, particularly for genes dependent on CREB and ATF transcription factors. Normal huntingtin interacts with CREB-binding protein (CBP) to support CREB-mediated transcription at promoters containing cAMP-responsive elements (CREs), enhancing histone acetyltransferase activity to promote gene expression essential for neuronal survival.^[45] This interaction is mediated in part by huntingtin-associated protein 1 (HAP1), which supports huntingtin's association with CBP and the general transcriptional machinery, including TAFII130, at promoter regions such as those of the enkephalin gene.^[45] Through these mechanisms, huntingtin contributes to the activation of CREB/ATF-dependent pathways that regulate neuronal function and plasticity.^[16] Huntingtin further influences gene expression by facilitating histone acetylation, primarily through modulation of Sp1 and REST/NRSF (repressor element-1 silencing transcription factor, also known as neuron-restrictive silencer factor). In normal conditions, huntingtin interacts with Sp1 to enhance its binding to coactivators like TAFII130 and CBP, promoting acetylation of histones at target promoters and thereby increasing transcription of neuronal genes such as those encoding the dopamine D2 receptor and nerve growth factor receptor.^[46] Concurrently, cytoplasmic huntingtin binds REST/NRSF, sequestering it away from nuclear NRSE (neuron-restrictive silencer element) sites to prevent repression and allow expression of neuron-specific genes, including brain-derived neurotrophic factor (BDNF).^[46] This dual modulation ensures appropriate chromatin accessibility and fine-tunes neuronal gene expression during development and maintenance.^[46] Beyond direct transcriptional control, huntingtin participates in chromatin remodeling and DNA repair processes that indirectly support gene regulation. As a scaffolding protein, huntingtin integrates into the ATM-dependent oxidative DNA damage response pathway, facilitating repair of DNA lesions that could otherwise disrupt chromatin structure and transcription.^[47] It interacts with components of this pathway, including those linked to p53 activation, to maintain genomic stability and enable proper chromatin reconfiguration for ongoing gene expression.^[47] These functions highlight huntingtin's broader role in preserving epigenetic integrity. During embryogenesis, huntingtin is essential for the differentiation of striatal neurons, particularly medium spiny neurons in the basal ganglia. Studies using huntingtin-null mouse embryonic stem cells demonstrate impaired neural progenitor formation, with differentiation efficiency dropping below 10% compared to over 95% in wild-type cells, while non-neural lineages like cardiac and pancreatic progenitors remain unaffected.^[48] This selectivity underscores huntingtin's necessity in neural-specific transcriptional programs, including REST/NRSF modulation, to drive striatal neurogenesis and establish proper brain circuitry.^[48]

Disease Associations

Huntington's Disease Mechanism

Huntington's disease (HD) arises primarily from a gain-of-function toxicity conferred by the expanded polyglutamine (polyQ) tract in mutant huntingtin (mHTT), which promotes the formation of intranuclear inclusions that disrupt neuronal homeostasis. These inclusions, first identified in postmortem HD brains, consist of aggregated mHTT fragments and associated proteins, contributing to cellular dysfunction rather than serving solely as protective sinks. The polyQ expansion alters mHTT's conformation, enhancing its propensity to misfold and aggregate, which sequesters essential cellular components and triggers proteotoxic stress in neurons. A key aspect of this toxicity involves proteolytic cleavage of mHTT, generating N-terminal fragments such as the exon 1 product, which are highly aggregation-prone and translocate to the nucleus. These fragments sequester transcriptional co-activators like CREB-binding protein (CBP), impairing histone acetylation and leading to widespread transcriptional dysregulation, including reduced expression of neuroprotective genes such as brain-derived neurotrophic factor (BDNF). Loss of BDNF transcription, mediated by mHTT's interference with the REST/NRSF repressor complex, exacerbates neuronal vulnerability by diminishing support for synaptic plasticity and survival signaling.^[49] This sequestration and dysregulation culminate in progressive neuronal death, particularly in the striatum. mHTT also sensitizes neurons to excitotoxicity, where excessive glutamate signaling through NMDA receptors triggers calcium overload and downstream apoptotic pathways. In HD, striatal medium spiny neurons (MSNs) exhibit heightened NMDA receptor activity, rendering them selectively vulnerable compared to other neuronal populations. This leads to caspase activation, including caspase-3 and -6, which further cleave mHTT into toxic fragments, amplifying a vicious cycle of proteolysis, aggregation, and cell death.^[50] The genetic basis involves CAG repeat expansions in the HTT gene exceeding 36 glutamines (with 36-39 showing reduced penetrance), with disease penetrance and onset inversely correlated to repeat length. Typical adult-onset HD features 40-50 CAG repeats, manifesting symptoms around 30-50 years of age, while expansions greater than 60 repeats cause juvenile-onset disease, often before age 20, with more severe progression.

Broader Pathological Roles

Huntingtin haploinsufficiency during development has been implicated in congenital anomalies through studies using mouse models. Complete knockout of the Htt gene in mice results in embryonic lethality at early stages due to defects in extra-embryonic tissues, underscoring the protein's essential role in early embryogenesis.^[51] Heterozygous Htt+/- mice are viable but exhibit subtle phenotypes, including altered synaptic vesicle endocytosis in striatal neurons, suggesting dosage sensitivity in neural development.^[52] Conditional inactivation of Htt in neural crest-derived lineages leads to congenital hydrocephalus, linking reduced huntingtin levels to brain structural anomalies.^[53] Similarly, loss of huntingtin function in cardiac contexts, as observed in models reducing normal Htt alongside mutant forms, contributes to cardiomyopathy-like defects, potentially tying haploinsufficiency to congenital heart issues.^[54] Beyond Huntington's disease, expanded polyglutamine (polyQ) tracts in huntingtin share pathogenic mechanisms with other polyQ disorders, such as spinocerebellar ataxia type 1 (SCA1) caused by polyQ in ataxin-1. These shared pathways include protein misfolding, aggregation, transcriptional dysregulation, and impaired autophagy, leading to neuronal toxicity across disorders.^[55] However, huntingtin-specific overlaps are evident in dentatorubral-pallidoluysian atrophy (DRPLA), where polyQ expansions in atrophin-1 produce similar dentate nucleus pathology and choreoathetosis, with transcriptomic studies revealing downregulated gene sets common to HD, SCA1, and DRPLA, particularly in pathways for synaptic function and inflammation.^[56] Aging exacerbates huntingtin-related neurodegeneration through a decline in normal huntingtin levels, increasing late-life vulnerabilities to protein aggregation and cellular stress. In mouse models, huntingtin protein expression decreases with age in brain regions like the striatum and cortex, correlating with accelerated disease progression and heightened sensitivity to toxic insults.^[57] This age-dependent reduction may contribute to broader neurodegenerative risks, as evidenced by overlaps between HD and amyotrophic lateral sclerosis (ALS), where HD cohorts show overrepresentation of ALS pathology, including TDP-43 aggregates in motor neurons, suggesting shared mechanisms like RNA processing defects and excitotoxicity.^[58] Co-occurrence cases often feature atypical TDP-43 distribution in older HD patients, highlighting huntingtin's role in intersecting pathways that promote motor neuron vulnerability.^[59] Recent post-2020 research has illuminated huntingtin's protective roles against cancer via autophagy regulation. Patients with polyQ disorders, including HD, exhibit markedly reduced cancer incidence, potentially due to upregulated chaperone-mediated autophagy that clears oncogenic proteins and suppresses tumorigenesis.^[60] In cellular models, normal huntingtin promotes autophagosome formation and lysosomal function, counteracting cancer progression; its dysregulation in polyQ expansions enhances this suppressive effect, linking haploinsufficiency or mutant forms to altered tumor suppression.^[61]

Interactions

Protein Binding Partners

Huntingtin (HTT) interacts with a diverse array of proteins, with over 200 binding partners identified through methods such as yeast two-hybrid screening and mass spectrometry, reflecting its role as a multifunctional scaffold protein. These interactions often occur via specific domains in the N-terminal region of HTT, including the polyglutamine (polyQ) tract, and can be modulated by the length of this tract in disease contexts. Key transport-related binding partners include huntingtin-associated protein 1 (HAP1) and p150^Glued, a subunit of the dynactin complex. HAP1 binds to the N-terminal region of HTT (amino acids 1-90), facilitating vesicular sorting along microtubules, with binding affinity increasing in the presence of expanded polyQ repeats.^[62] Similarly, p150^Glued interacts with HTT either directly or through HAP1, supporting microtubule-based intracellular transport; this association is mediated by the N-terminal domain of HTT and is essential for dynein-dynactin motor function. Among transcription factors, HTT binds CREB-binding protein (CBP) and p300, which are histone acetyltransferases involved in gene activation. These interactions occur via the glutamine-rich and acetyltransferase domains of CBP/p300, with mutant HTT exhibiting stronger sequestration of CBP into aggregates due to expanded polyQ, thereby altering transcriptional regulation. HTT also associates with specificity protein 1 (Sp1), binding to amino acids 1-171 and showing enhanced affinity with polyQ expansion, which disrupts Sp1's promoter binding and downstream gene expression. Additionally, HTT interacts with RE1-silencing transcription factor (REST), primarily in the cytoplasm via intermediary proteins, where wild-type HTT reduces nuclear localization of REST to prevent gene repression; polyQ expansion impairs this binding, leading to increased REST activity. Other notable partners include huntingtin-interacting protein 1 (HIP1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). HIP1 binds the N-terminal fragment of HTT (amino acids 1-540) to support clathrin-mediated endocytosis, though this affinity decreases with polyQ expansion. GAPDH associates with the polyproline-rich region of HTT (amino acids 175-264), with binding strengthened by expanded polyQ, influencing apoptosis signaling pathways.^[63] Huntingtin-associated protein 40 (HAP40) binds the central region of HTT, stabilizing its elongated α-helical structure and facilitating protein-protein interactions.^[3] These context-specific alterations in binding affinity highlight how polyQ length modulates HTT's interactome, often exacerbating pathological associations without directly invoking functional outcomes.

Functional Networks

Huntingtin (HTT) integrates into the brain-derived neurotrophic factor (BDNF) signaling pathway, where it plays a critical role in facilitating the vesicular transport and receptor dynamics necessary for neurotrophic support and neuronal survival. Wild-type HTT enhances the anterograde transport of BDNF-containing vesicles along microtubules in cortical neurons, increasing their velocity and reducing pauses to ensure efficient delivery to synapses, particularly in cortico-striatal projections.^[64] This transport mechanism supports BDNF release and subsequent activation of its receptor, tropomyosin receptor kinase B (TrkB). Additionally, HTT is essential for the retrograde trafficking of activated TrkB receptors in striatal dendrites, forming a complex with dynein intermediate chain 1B to maintain signaling integrity.^[65] BDNF-TrkB activation downstream leads to phosphorylation and activation of cAMP response element-binding protein (CREB), promoting transcription of survival genes and providing neuroprotection against cellular stress. Disruption of these processes in the absence of functional HTT impairs neurotrophic signaling and neuronal viability. In the autophagy-lysosome pathway, HTT acts as a scaffold to coordinate the initiation and execution of macroautophagy, particularly for selective clearance of protein aggregates. HTT binds to unc-51 like autophagy activating kinase 1 (ULK1), the primary kinase that initiates autophagy under stress conditions, promoting its activation by competing with mTOR for binding. HTT also interacts with p62 (SQSTM1), facilitating ULK1 recruitment to ubiquitinated cargoes recognized by p62. This scaffolding enhances autophagosome formation and fusion with lysosomes, promoting efficient degradation of ubiquitinated substrates. Beclin-1, a component of the phosphatidylinositol 3-kinase (VPS34) complex, acts downstream to generate phosphatidylinositol 3-phosphate (PI3P), recruiting additional autophagy machinery to support progression. These interactions ensure cellular homeostasis by clearing damaged organelles and misfolded proteins, with HTT's scaffolding role being vital for maximal autophagy flux during nutrient deprivation or proteotoxic stress. HTT modulates the Wnt/β-catenin signaling pathway during embryonic development, influencing cellular proliferation and differentiation in neural tissues. Normal HTT promotes the degradation of β-catenin, a key effector of canonical Wnt signaling, through interactions that facilitate its ubiquitination and proteasomal clearance, thereby preventing excessive pathway activation. This regulatory function is essential for proper patterning of the central nervous system, including cortical layer formation and neuronal migration. In parallel, HTT links to the mammalian target of rapamycin (mTOR) pathway for energy sensing, as its scaffolding of ULK1 integrates with mTORC1 inhibition during low-energy states to trigger autophagy. When mTOR activity is suppressed by nutrient scarcity, HTT-ULK1 interactions amplify autophagic responses, balancing energy homeostasis and cellular resource allocation. Recent proteomic analyses have revealed HTT's involvement in networks regulating DNA repair/remodeling and RNA processing, potentially contributing to genomic and transcriptional stability in neurons (as of 2024).^[66] These connections highlight HTT's role in developmental and metabolic signaling networks. Beyond the brain, HTT participates in systemic networks regulating metabolism in peripheral tissues, notably influencing insulin signaling in the liver. In hepatocytes, HTT maintains zonal gene expression patterns critical for metabolic zonation, where its presence supports pericentral processes like gluconeogenesis and lipid handling. Loss of HTT disrupts these patterns, leading to altered adhesion, fibrosis, and impaired insulin responsiveness, as evidenced by shifts in glucose and lipid metabolism. HTT's expression in the liver coordinates with insulin pathways to regulate energy storage and release, ensuring systemic glucose homeostasis. This peripheral role underscores HTT's broader involvement in inter-organ metabolic communication, with implications for whole-body energy balance.^[67]

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We will discuss a model in which huntingtin acts as a scaffold to coordinate the function of molecular motors during vesicular transport. Analysis of the ...
[35]
Huntingtin differentially regulates the axonal transport of a sub-set of ...
Huntingtin regulates the axonal movement of a particular sub-set of Rab-containing vesicles. Previous work showed that HTT associates with MT motors kinesin-1 ...
[36]
Huntingtin-associated protein-1 (HAP1) regulates endocytosis and ...
In line with a physiological function of the HAP1-clathrin interaction this study detected a dramatic reduction in vesicle retrieval and endocytosis in adrenal ...
[37]
Huntingtin is required for ER-to-Golgi transport and for secretory ...
Huntingtin is a large membrane-associated scaffolding protein that associates with endocytic and exocytic vesicles and modulates their trafficking along ...
[38]
Huntingtin-associated protein 1 regulates exocytosis, vesicle ...
HAP1 regulates exocytosis by influencing the morphological docking of vesicles at the plasma membrane, the ability of vesicles to be released rapidly upon ...
[39]
Huntingtin Functions as a Scaffold for Selective Macroautophagy
Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. ... Huntingtin expression stimulates endosomal-lysosomal ...
[40]
The Regulation of Autophagosome Dynamics by Huntingtin and ...
We show that both huntingtin (htt) and its adaptor protein huntingtin-associated protein-1 (HAP1) copurify and colocalize with autophagosomes in neurons.
[41]
Huntingtin contains an ubiquitin-binding domain and regulates ...
We demonstrate that the HTT protein can directly bind ubiquitin through a ubiquitin-binding domain (UBD) that interacts with ubiquitinated or ubiquitin- ...Missing: Jana | Show results with:Jana
[42]
Mouse mutant embryos lacking huntingtin are rescued from lethality ...
Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues ... Mice, Knockout; Nerve Tissue Proteins / biosynthesis ...
[43]
Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons ...
Recent data in invertebrates demonstrated that huntingtin (htt) is essential for fast axonal trafficking. Here, we provide direct and functional evidence ...
[44]
Huntingtin and the molecular pathogenesis of Huntington's disease: Fourth in Molecular Medicine Review Series: EMBO reports: Vol 5, No 10
### Summary of Normal Huntingtin's Role in Transcriptional Activation
[45]
Transcriptional dysregulation in Huntington's disease: a failure of ...
Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. ... Sp1 regulates human huntingtin gene expression. J ...
[46]
Huntingtin is a scaffolding protein in the ATM oxidative DNA damage ...
Nov 21, 2016 · We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human ...Huntingtin Is A Scaffolding... · N17-Phosphorylated... · Huntingtin Participates In...
[47]
Huntingtin Is Required for Neural But Not Cardiac/Pancreatic ...
Feb 21, 2017 · The data suggests Htt is essential for neural but not cardiac/pancreatic progenitor differentiation of embryonic stem cells in vitro.
[48]
https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2017.00033/full
[49]
https://doi.org/10.1126/science.1059581
[50]
Is Huntington disease a developmental disorder? - PMC
The most compelling proof that huntingtin is essential for early development is that inactivation of the murine gene results in defects in extra-embryonic ...
[51]
Loss of huntingtin function slows synaptic vesicle endocytosis in ...
The loss of function phenotype we observe suggests that it may result from htt haploinsufficiency. In support, heterozygous htt knockout mice display a ...Missing: cardiac | Show results with:cardiac
[52]
Congenital hydrocephalus associated with abnormal ...
Here we show that conditional inactivation of the Hdh gene in Wnt1 cell lineages results in congenital hydrocephalus, implicating huntingtin for the first time ...Missing: haploinsufficiency cardiac
[53]
Targeted Genetic Reduction of Mutant Huntingtin Lessens Cardiac ...
Targeted genetic reduction of mutant huntingtin lessens cardiac pathology in the BACHD mouse model of Huntington's disease.
[54]
Polyglutamine (PolyQ) Diseases: Navigating the Landscape of ...
Jul 12, 2024 · Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins.
[55]
Juvenile Huntington's Disease and Other PolyQ Diseases, Update ...
Venn diagrams visualizing the overlap between downregulated genes in HD and SCA1; (B) and for overlapping genes downregulated in SCA1 and DRPLA (D). ClueGO ...
[56]
Striatal Mutant Huntingtin Protein Levels Decline with Age in ...
May 19, 2018 · A general decline in mutant HTT levels in striatum and cortex is observed that may contribute to disease progression in homozygous knock-in HD ...
[57]
More than a co-incidence? Exploring the increased frequency of ...
Dec 21, 2022 · Amyotrophic lateral sclerosis is over‐represented in two Huntington's disease brain bank cohorts: further evidence to support genetic pleiotropy.
[58]
Coexistence of Huntington's disease and amyotrophic lateral sclerosis
Mar 13, 2012 · We suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution.
[59]
Upregulated Chaperone-Mediated Autophagy May Perform a Key ...
Oct 27, 2023 · Incidence of cancer is markedly reduced in patients with the hereditary neurodegenerative polyglutamine (polyQ) diseases.
[60]
Navigating the neuronal recycling bin: Another look at huntingtin in ...
This review explores normal HTT's multifaceted role in neuronal autophagy, from its potential involvement in autophagy induction, its capacity to influence ...
[61]
https://www.tandfonline.com/doi/full/10.1080/27694127.2025.2472450
[62]
https://doi.org/10.1038/378398a0
[63]
https://doi.org/10.3390/ijms241713060
[64]
Peripheral Expression of Mutant Huntingtin is a Critical Determinant ...
Jul 12, 2019 · The available evidence, however, indicates the adipose tissue and liver to be the major determinants of these peripheral manifestations.