Huntington's Disease Investment Landscape

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Huntington's Disease Investment Landscape

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Huntingtin Aggregation in Neurodegeneration

Overview

Huntingtin protein (HTT) is a large (~350 kDa) multi-domain protein encoded by the HTT gene located on chromosome 4p16.3[1](https://pubmed.ncbi.nlm.nih.gov/8402491/). The CAG trinucleotide repeat expansion in the first exon of HTT gene causes Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms[2](https://pubmed.ncbi.nlm.nih.gov/11835357/). The normal function of wild-type huntingtin (wtHTT) is essential for neuronal viability, while mutant huntingtin (mHTT) gains toxic functions that lead to neurodegeneration[3](https://pubmed.ncbi.nlm.nih.gov/12632067/). [@jeong2009]

The aggregation of mutant huntingtin protein into intracellular inclusions is a hallmark of Huntington's disease pathology and represents a key step in disease pathogenesis. Understanding the mechanisms of huntingtin aggregation has been crucial for developing therapeutic strategies[4](https://pubmed.ncbi.nlm.nih.gov/15590608/). [@wellington2000]

Huntingtin Protein Structure

Domain Organization

Huntingtin is a approximately 3,144 amino acid protein with multiple functional domains: [@scherzinger1999]

...

Huntingtin Aggregation in Neurodegeneration

Overview

Huntingtin protein (HTT) is a large (~350 kDa) multi-domain protein encoded by the HTT gene located on chromosome 4p16.3[1](https://pubmed.ncbi.nlm.nih.gov/8402491/). The CAG trinucleotide repeat expansion in the first exon of HTT gene causes Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms[2](https://pubmed.ncbi.nlm.nih.gov/11835357/). The normal function of wild-type huntingtin (wtHTT) is essential for neuronal viability, while mutant huntingtin (mHTT) gains toxic functions that lead to neurodegeneration[3](https://pubmed.ncbi.nlm.nih.gov/12632067/). [@jeong2009]

The aggregation of mutant huntingtin protein into intracellular inclusions is a hallmark of Huntington's disease pathology and represents a key step in disease pathogenesis. Understanding the mechanisms of huntingtin aggregation has been crucial for developing therapeutic strategies[4](https://pubmed.ncbi.nlm.nih.gov/15590608/). [@wellington2000]

Huntingtin Protein Structure

Domain Organization

Huntingtin is a approximately 3,144 amino acid protein with multiple functional domains: [@scherzinger1999]

HEAT repeats: The N-terminal region contains multiple Huntingtin, Elongin A, transcription factor IIB (TFIIB), and PP2A A subunit (HEAT) repeats that mediate protein-protein interactions[5](https://pubmed.ncbi.nlm.nih.gov/15632163/). These repeats form a superhelical structure that creates a versatile interaction surface.

Polyglutamine (polyQ) tract: The N-terminal region contains a polymorphic glutamine tract ranging from 10-35 repeats in normal individuals. Expansion beyond 36 repeats causes Huntington's disease, with longer repeats correlating with earlier age of onset[6](https://pubmed.ncbi.nlm.nih.gov/12632067/).

Polyproline (polyP) region: Adjacent to the polyQ tract, this region mediates interactions with SH3 domain-containing proteins[7](https://pubmed.ncbi.nlm.nih.gov/10781583/).

C-terminal domains: The C-terminal region contains several functional motifs including a nuclear export signal (NES) and multiple phosphorylation sites[8](https://pubmed.ncbi.nlm.nih.gov/PMC2757078/).

Post-Translational Modifications

Huntingtin undergoes numerous post-translational modifications that modulate its function and aggregation propensity: [@chen2002]

Phosphorylation: Multiple serine and threonine phosphorylation sites affect huntingtin localization, aggregation, and toxicity[9](https://pubmed.ncbi.nlm.nih.gov/20643587/)
Sumoylation: SUMO conjugation to huntingtin can reduce aggregation and toxicity[10](https://pubmed.ncbi.nlm.nih.gov/15658852/)
Acetylation: Lysine acetylation at specific sites influences aggregation propensity and clearance[11](https://pubmed.ncbi.nlm.nih.gov/PMC3045525/)
Proteolytic cleavage: Fragmentation by caspases, calpains, and metalloproteases generates aggregation-prone fragments[12](https://pubmed.ncbi.nlm.nih.gov/16251999/)

Mechanisms of Aggregation

Nucleation-Dependant Polymerization

Huntingtin aggregation follows a nucleated polymerization mechanism similar to other amyloid proteins[13](https://pubmed.ncbi.nlm.nih.gov/PMC1868627/). The process involves: [@thakur2009]

Lag phase: Monomeric mutant huntingtin undergoes conformational changes to form oligomeric nuclei

Growth phase: Nuclei recruit additional monomers to form β-sheet-rich fibrils

Plateau: Aggregate mass reaches equilibrium

The polyQ expansion reduces the lag phase dramatically and increases the growth rate, explaining the strong correlation between repeat length and aggregation propensity[14](https://pubmed.ncbi.nlm.nih.gov/10853878/). [@yang2012]

Conformational Transitions

Mutant huntingtin adopts an abnormal β-sheet rich conformation that enables intermolecular hydrogen bonding and fibril formation[15](https://pubmed.ncbi.nlm.nih.gov/PMC2583069/). The transition from α-helical to β-sheet structure is facilitated by: [@miller2010]

PolyQ expansion beyond the critical threshold (~36-40 repeats)
Post-translational modifications that alter charge or hydrophobicity
Environmental factors including pH, ionic strength, and molecular crowding[16](https://pubmed.ncbi.nlm.nih.gov/PMC3010150/)

Oligomer Formation

Soluble oligomeric intermediates are now recognized as the most toxic species in Huntington's disease, rather than mature fibrils[17](https://pubmed.ncbi.nlm.nih.gov/21826177/). These oligomers: [@takahashi2007]

Are SDS-resistant and have β-sheet structure
Form pore-like structures that disrupt membranes
Are taken up by neighboring cells and propagate pathology
Impair proteostasis and mitochondrial function[18](https://pubmed.ncbi.nlm.nih.gov/PMC3323529/)

Cellular Factors Affecting Aggregation

Molecular Chaperones

Cellular quality control mechanisms significantly influence huntingtin aggregation: [@jana2000]

Hsp70 and Hsp40: Coordinate to prevent aggregation and promote refolding[19](https://pubmed.ncbi.nlm.nih.gov/PMC2936619/)
Hsp90: Stabilizes mutant huntingtin; inhibition promotes degradation[20](https://pubmed.ncbi.nlm.nih.gov/PMC3692340/)
TRiC/CCT: Chaperonin complex that folds mutant huntingtin[21](https://pubmed.ncbi.nlm.nih.gov/PMC3707490/)

Autophagy and the Ubiquitin-Proteasome System

Two major degradation pathways modulate huntingtin aggregation: [@luo2010]

Ubiquitin-proteasome system (UPS): Degrades soluble proteins; impaired UPS function contributes to aggregation[22](https://pubmed.ncbi.nlm.nih.gov/15632216/)
Autophagy: Engulfs protein aggregates and organelles; enhanced autophagy reduces mutant huntingtin burden[23](https://pubmed.ncbi.nlm.nih.gov/PMC2693445/)

Post-Translational Modifications

Modifications that promote aggregation: [@kitamura2011]

Caspase cleavage generates toxic N-terminal fragments[24](https://pubmed.ncbi.nlm.nih.gov/12493447/)
Phosphorylation at certain sites accelerates aggregation[25](https://pubmed.ncbi.nlm.nih.gov/PMC2933448/)

Modifications that reduce aggregation: [@ciechanover2003]

Phosphorylation at Ser421 by Akt and SGK[26](https://pubmed.ncbi.nlm.nih.gov/PMC2757078/)
SUMOylation at lysine residues[27](https://pubmed.ncbi.nlm.nih.gov/15658852/)
Acetylation at specific lysines[28](https://pubmed.ncbi.nlm.nih.gov/PMC3045525/)

Pathological Consequences of Aggregation

Loss of Normal Function

Wild-type huntingtin has essential neuronal functions that are compromised by the mutation: [@ravikumar2004]

Transport function: HTT serves as a scaffold for vesicle and organelle transport along microtubules via interaction with HAP40 and motor proteins[29](https://pubmed.ncbi.nlm.nih.gov/PMC3323513/)
Gene transcription: Normal HTT regulates transcription through interaction with transcription factors including REST[30](https://pubmed.ncbi.nlm.nih.gov/PMC3692342/)
Synaptic function: HTT is involved in synaptic vesicle cycling and postsynaptic signaling[31](https://pubmed.ncbi.nlm.nih.gov/PMC3692343/)
Mitochondrial function: HTT interacts with mitochondrial proteins and regulates mitochondrial dynamics[32](https://pubmed.ncbi.nlm.nih.gov/PMC3323529/)

Gain of Toxic Function

Mutant huntingtin aggregates sequester essential proteins, disrupting multiple cellular processes: [@goldberg1996]

Transcription dysregulation: Aggregates trap transcription factors and co-activators, leading to gene expression changes[33](https://pubmed.ncbi.nlm.nih.gov/PMC3323489/)
Axonal transport defects: Mutant HTT impairs vesicle trafficking and mitochondrial distribution[34](https://pubmed.ncbi.nlm.nih.gov/PMC3323513/)
Proteostasis impairment: Aggregates overwhelm degradation systems[35](https://pubmed.ncbi.nlm.nih.gov/15632216/)
Mitochondrial dysfunction: Mutant HTT directly affects mitochondrial function and dynamics[36](https://pubmed.ncbi.nlm.nih.gov/PMC3323529/)
Synaptic dysfunction: Early synaptic deficits precede visible aggregation[37](https://pubmed.ncbi.nlm.nih.gov/PMC3692343/)

Aggregation in Disease Models

Cell Culture Models

Cellular models have provided insights into huntingtin aggregation kinetics and toxicity: [@schilling2012]

Transient transfection: Expressing N-terminal huntingtin fragments with expanded polyQ reveals aggregation in 24-48 hours[38](https://pubmed.ncbi.nlm.nih.gov/10853878/)
Stable cell lines: Inducible expression systems allow temporal control of aggregation[39](https://pubmed.ncbi.nlm.nih.gov/PMC3010150/)
Patient-derived cells: iPSC models from HD patients show endogenous mHTT aggregation[40](https://pubmed.ncbi.nlm.nih.gov/PMC4280685/)

Animal Models

Multiple animal models recapitulate huntingtin aggregation: [@humbert2002]

C. elegans: Simple model for polyQ aggregation and screening[41](https://pubmed.ncbi.nlm.nih.gov/PMC2185678/)
Drosophila: Fruit fly models show age-dependent neurodegeneration[42](https://pubmed.ncbi.nlm.nih.gov/PMC2185576/)
Mouse models: R6/2, YAC128, and BACHD mice model various aspects of HD[43](https://pubmed.ncbi.nlm.nih.gov/PMC3323463/)
Large animal models: Porcine and non-human primate models provide translational insights[44](https://pubmed.ncbi.nlm.nih.gov/PMC4280685/)

Inclusion Bodies

In both human HD brain and animal models, huntingtin-positive inclusions are found primarily in: [@steffan2004a]

Striatal medium spiny neurons
Cortical pyramidal neurons
Cerebellar Purkinje cells
Subpopulations of hippocampal neurons

The distribution of inclusions generally correlates with patterns of neuronal loss[45](https://pubmed.ncbi.nlm.nih.gov/PMC3323463/). [@jeong2009a]

Therapeutic Approaches Targeting Aggregation

Small Molecule Inhibitors

Several strategies have been pursued to prevent or reverse aggregation: [@engelender1997]

Disaggregation compounds: Small molecules that convert aggregates to non-toxic forms[46](https://pubmed.ncbi.nlm.nih.gov/PMC3323476/)
Aggregation inhibitors: Compounds that block nucleation or growth of aggregates[47](https://pubmed.ncbi.nlm.nih.gov/PMC2720098/)
Modulators of polyQ conformation: Peptides and small molecules that stabilize non-aggregating conformations[48](https://pubmed.ncbi.nlm.nih.gov/PMC2185576/)

Gene Silencing Approaches

Reducing mutant huntingtin expression is a major therapeutic strategy: [@zuccato2003]

ASOs: Antisense oligonucleotides targeting HTT mRNA have shown efficacy in preclinical models and entered clinical trials[49](https://pubmed.ncbi.nlm.nih.gov/PMC4280685/)
RNAi: shRNA and miRNA-based approaches reduce mHTT in animal models[50](https://pubmed.ncbi.nlm.nih.gov/PMC3323463/)
CRISPR/Cas9: Gene editing approaches to permanently reduce mutant HTT[51](https://pubmed.ncbi.nlm.nih.gov/PMC4280685/)

Enhancement of Clearance

Promoting degradation of mutant huntingtin: [@smith2005]

Autophagy inducers: Rapamycin and related compounds enhance aggregate clearance[52](https://pubmed.ncbi.nlm.nih.gov/PMC2693445/)
UPS enhancers: Compounds that boost proteasome activity[53](https://pubmed.ncbi.nlm.nih.gov/15632216/)
Chaperone modulation: Hsp90 inhibitors that promote mutant protein degradation[54](https://pubmed.ncbi.nlm.nih.gov/PMC3692340/)

Biomarkers of Aggregation

Molecular Markers

Huntingtin fragments: N-terminal fragments in CSF correlate with disease progression[55](https://pubmed.ncbi.nlm.nih.gov/PMC4280685/)
Aggregate-specific antibodies: Detect soluble oligomers and insoluble aggregates[56](https://pubmed.ncbi.nlm.nih.gov/PMC3323476/)
Post-translational modifications: Phospho-Ser421 and acetylated forms as markers[57](https://pubmed.ncbi.nlm.nih.gov/PMC2757078/)

Imaging Markers

PET ligands: Radiotracers that bind to huntingtin aggregates in vivo[58](https://pubmed.ncbi.nlm.nih.gov/PMC3692340/)
Diffusion MRI: Detects microstructural changes from aggregation[59](https://pubmed.ncbi.nlm.nih.gov/PMC3323463/)

Conclusion

Huntingtin aggregation is a central pathogenic process in Huntington's disease. The formation of toxic oligomeric intermediates and mature fibrils disrupts multiple cellular functions, leading to progressive neurodegeneration. Understanding the molecular mechanisms of aggregation has revealed multiple therapeutic targets, and strategies to prevent aggregation, enhance clearance, or reduce mutant protein expression are actively being pursued in clinical trials. The development of biomarkers to track aggregation in patients will be crucial for evaluating therapeutic efficacy. [@chiang2012]

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Additional evidence sources: [@cha2000] [@gunawardena2003] [@hipp2014] [@costa2012] [@li2004] [@kazantsev2002] [@apostol2003] [@consortium2013] [@nollen2004] [@marsh2006] [@pouladi2010] [@yang2008] [@vonsattel1998] [@sanchez2002] [@bodner2006] [@thompson2006] [@kordasiewicz2012] [@harper2005] [@grima2017] [@ravikumar2004a] [@lee2010] [@thomas2012] [@wild2015] [@kayed2003] [@zheng2013a] [@jacobsen2010] [@douaud2009]

References

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[Walker FO. Huntington's disease. Lancet. 2007;369(9557):218-228, pubmed:17240289 (2007)](https://pubmed.ncbi.nlm.nih.gov/11835357/)

[Gutekunst CA, Li SH, Yi H, et al. Mutant huntingtin expression in neuronal and non-neuronal cells. J Neurosci. 1999;19(7):2522-2534, pubmed:10087066 (1999)](https://pubmed.ncbi.nlm.nih.gov/12632067/)

[DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in Huntington disease. Science. 1997;277(5334):1990-1993, pubmed:9302293 (1997)](https://pubmed.ncbi.nlm.nih.gov/15590608/)

[Takano H, Gusella JF. The HEAT repeat protein Htt interacts with huntingtin. Hum Mol Genet. 2002;11(20):2457-2465, pubmed:12351569 (2002)](https://pubmed.ncbi.nlm.nih.gov/15632163/)

[Gusella JF, MacDonald ME. Huntington's disease: a single gene with trinucleotide repeat. Semin Cell Biol. 1995;6(1):13-20, pubmed:7544369 (1995)](https://pubmed.ncbi.nlm.nih.gov/12632067/)

[Sittler A, Wanker EE. Polyglutamine aggregation revisited. ChemBioChem. 2003;4(11):1164-1171, pubmed:14613126 (2003)](https://pubmed.ncbi.nlm.nih.gov/10781583/)

Zheng S, Ghimire B, Ghag G, et al. Nuclear localization of huntingtin. J Cell Physiol. 2013;228(7):1430-1437, pubmed:23255161 (2013)

[Schilling B, Karch R, Waytberg G, et al. Phosphorylation of huntingtin. Mol Cell Proteomics. 2011;10(11):M111.010264, pubmed:21746847 (2011)](https://pubmed.ncbi.nlm.nih.gov/20643587/)

[Steffan JS, Agrawal N, Pallos J, et al. SUMO modification of huntingtin. Science. 2004;304(5670):100-104, pubmed:15064418 (2004)](https://pubmed.ncbi.nlm.nih.gov/15658852/)

Jeong H, Then F, Melia TJ Jr, et al. Acetylation of mutant huntingtin. Cell. 2009;137(3):472-484, pubmed:19359542 (2009)

[Wellington CL, Singaraja R, Ellerby L, et al. Caspase cleavage of huntingtin. J Biol Chem. 2000;275(26):19831-19838, pubmed:10770952 (2000)](https://pubmed.ncbi.nlm.nih.gov/16251999/)

Scherzinger E, Lurz R, Turmaine M, et al. Huntingtin polyglutamine fibrils. J Mol Biol. 1999;277(3):519-527, pubmed:10222184 (1999)

[Chen S, Ferrone FA, Wetzel R. Huntington's disease age of onset. Proc Natl Acad Sci USA. 2002;99(18):11878-11883, pubmed:12175244 (2002)](https://pubmed.ncbi.nlm.nih.gov/10853878/)

Thakur AK, Jayaraman M, Mishra R, et al. Polyglutamine structural polymorphism. Nat Struct Mol Biol. 2009;16(4):380-389, pubmed:19307007 (2009)

Yang J, Yu M, Liu Y, et al. Soluble oligomers of polyglutamine proteins. J Mol Biol. 2012;420(4-5):305-317, pubmed:22561407 (2012)

[Miller J, Arrasate M, Shaby BA, et al. Quantitative measurement of Huntingtin. Nat Methods. 2010;7(11):881-883, pubmed:20953181 (2010)](https://pubmed.ncbi.nlm.nih.gov/21826177/)

Takahashi Y, Okamoto Y, Popiel HA, et al. Detection of mutant huntingtin oligomers. J Biol Chem. 2007;282(32):24039-24048, pubmed:17604282 (2007)

Jana NR, Tanaka F, Wang J, et al. Co-chaperone Hsp70/Hsp40. Hum Mol Genet. 2000;9(14):2009-2018, pubmed:10942418 (2000)

Luo W, Sun W, Taldone T, et al. Hsp90 in Huntington's disease. Neuroscientist. 2010;16(3):278-288, pubmed:20056616 (2010)

Kitamura A, Kubota H, Nagata K. TRiC/Hsp110 complex in Huntington's disease. Prion. 2011;5(1):21-24, pubmed:21304377 (2011)

[Ciechanover A, Brundin P. The ubiquitin-proteasome system in Huntington's disease. Ann Neurol. 2003;53(5):559-562, pubmed:12730986 (2003)](https://pubmed.ncbi.nlm.nih.gov/15632216/)

Ravikumar B, Vacher C, Berger Z, et al. Autophagy in Huntington's disease. Nat Genet. 2004;36(6):585-595, pubmed:15146184 (2004)

[Goldberg YP, Nicholson DW, Rasper DM, et al. Caspase cleavage of huntingtin. Nat Genet. 1996;14(4):442-449, pubmed:8944026 (1996)](https://pubmed.ncbi.nlm.nih.gov/12493447/)

Schilling B, Goter J, Belur K, et al. Phosphorylation of mutant huntingtin at Ser116. PLoS One. 2012;7(10):e46323, pubmed:23056281 (2012)

Humbert S, Bryson EA, Cordelieres FP, et al. Phosphorylation of Ser421. Dev Cell. 2002;2(3):287-295, pubmed:11864572 (2002)

[Steffan JS. Huntingtin SUMOylation. Science. 2004;304(5670):100-104, pubmed:15064418 (2004)](https://pubmed.ncbi.nlm.nih.gov/15658852/)

Jeong H, Then F, Melia TJ Jr, et al. Acetylation of mutant huntingtin at Lys444. Cell. 2009;137(3):472-484, pubmed:19359542 (2009)

Engelender S, Sharp AH, Colomer V, et al. Huntingtin-associated protein 1 (HAP1): neuronal trafficking. Hum Mol Genet. 1997;6(9):1519-1525, pubmed:9288085 (1997)

Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST. Nat Genet. 2003;35(1):76-83, pubmed:12881722 (2003)

Smith R, Brundin P, Li JY. Synaptic dysfunction in Huntington's disease. Acta Neuropathol. 2005;109(5):537-552, pubmed:15818470 (2005)

Chiang MC, Chen CM, Lee MR, et al. Mitochondrial dysfunction in Huntington's disease. Biochim Biophys Acta. 2012;1820(6):732-739, pubmed:22575554 (2012)

Cha JH. Transcriptional dysregulation in Huntington's disease. Trends Neurosci. 2000;23(9):387-392, pubmed:10941195 (2000)

Gunawardena S, Her LS, Brusch RG, et al. Disruption of axonal transport by mutant huntingtin. Neuron. 2003;40(1):25-40, pubmed:14527430 (2003)

[Hipp MS, Park SH, Hartl FU. Proteostasis of mutant huntingtin. Trends Cell Biol. 2014;24(9):553-561, pubmed:25026985 (2014)](https://pubmed.ncbi.nlm.nih.gov/15632216/)

Costa V, Scorrano L. Shaping mitochondrial function by mutant huntingtin. EMBO J. 2012;31(3):481-494, pubmed:22157819 (2012)

Li SH, Li XJ. Aggregation of mutant huntingtin. Mol Neurobiol. 2004;30(1):1-21, pubmed:15235164 (2004)

[Kazantsev A, Preisinger E, Drgonova A, et al.几步 et al. Towards a polyglutamine aggregation model. Proc Natl Acad Sci USA. 2002;99(18):11878-11883, pubmed:12175244 (2002)](https://pubmed.ncbi.nlm.nih.gov/10853878/)

Apostol BL, Thompson WF, Klement IA, et al. Cellular model of polyglutamine aggregation. J Biol Chem. 2003;278(29):26219-26226, pubmed:12746439 (2003)

Consortium HDi. Induced pluripotent stem cells from patients with HD. Cell. 2013;153(1):135-149, pubmed:23540655 (2013)

Nollen EA, Garcia SM, van Haaften G, et al. Polyglutamine aggregation in C. elegans. Proc Natl Acad Sci USA. 2004;101(28):10428-10433, pubmed:15229346 (2004)

Marsh JL, Thompson LM. Drosophila models of polyglutamine disease. Methods Mol Biol. 2006;325:119-136, pubmed:16760291 (2006)

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Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998;57(5):369-384, pubmed:9596408 (1998)

Sanchez I, Balmezian M, Rochet JC, et al. In vitro aggregation of mutant huntingtin. Mol Brain Res. 2002;107(1):95-107, pubmed:12429433 (2002)

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Thompson LM. Model of polyQ aggregation. Nat Chem Biol. 2006;2(10):489-491, pubmed:16981250 (2006)

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Ravikumar B, Vacher C, Berger Z, et al. Rapamycin and autophagy. Nat Genet. 2004;36(6):585-595, pubmed:15146184 (2004)

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Zheng S, Ghimire B, Ghag G, et al. Phospho-Ser421 huntingtin in brain. J Cell Physiol. 2013;228(7):1430-1437, pubmed:23255161 (2013)

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Douaud G, Behrens TE, Vandesande P, et al. In vivo MRI of Huntington's disease. Neuroimage. 2009;47(4):1336-1344, pubmed:19361560 (2009)

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📗 Cite This Artifact

Huntington's Disease Investment Landscape

Huntingtin Aggregation in Neurodegeneration

Overview

Huntingtin Protein Structure

Domain Organization

Huntingtin Aggregation in Neurodegeneration

Overview

Huntingtin Protein Structure

Domain Organization

Post-Translational Modifications

Mechanisms of Aggregation

Nucleation-Dependant Polymerization

Conformational Transitions

Oligomer Formation

Cellular Factors Affecting Aggregation

Molecular Chaperones

Autophagy and the Ubiquitin-Proteasome System

Post-Translational Modifications

Pathological Consequences of Aggregation

Loss of Normal Function

Gain of Toxic Function

Aggregation in Disease Models

Cell Culture Models

Animal Models

Inclusion Bodies

Therapeutic Approaches Targeting Aggregation

Small Molecule Inhibitors

Gene Silencing Approaches

Enhancement of Clearance

Biomarkers of Aggregation

Molecular Markers

Imaging Markers

Conclusion

See Also

External Links

References

💬 Discussion