Cited by 1,291Genetic Neurodegenerative DiseasesPrion Diseases and Protein MisfoldingGenetics and Neurodevelopmental Disorders

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Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo

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Scherzinger, Eberhard, Lurz, Rudi, Turmaine, Mark, Mangiarini, Laura, Hollenbach, Birgit, Hasenbank, Renate, Bates, Gillian P, Davies, Stephen W, Lehrach, Hans, Wanker, Erich E·1997·Cell

DOI 10.1016/s0092-8674(00)80514-0

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Abstract

The mechanism by which an elongated polyglutamine sequence causes neurodegeneration in Huntington's disease (HD) is unknown. In this study, we show that the proteolytic cleavage of a GST-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range. Electron micrographs of these aggregates revealed a fibrillar or ribbon-like morphology, reminiscent of scrapie prions and beta-amyloid fibrils in Alzheimer's disease. Subcellular fractionation and ultrastructural techniques showed the in vivo presence of these structures in the brains of mice transgenic for the HD mutation. Our in vitro model will aid in an eventual understanding of the molecular pathology of HD and the development of preventative strategies.

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BackgroundInfluential
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Self-citation
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Background
Identification of Human Proteins That Modify Misfolding and Proteotoxicity of Pathogenic Ataxin-1
Petrakis, S., Raskó, T., Russ, J., Friedrich, R. P., Strödicke, M., Riechers, S., Muehlenberg, K., Möller, A., Reinhardt, A., Vinayagam, A., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002897 · Cited by 34
“(HTT), ataxin-1 (ATXN1) and ataxin-3 (ATXN3) [7,8].”
Self-citation
Live cell imaging and biophotonic methods reveal two types of mutant huntingtin inclusions
Caron, N. S., Hung, C. L.-K., Atwal, R. S., & Truant, R. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt625 · Cited by 32
The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders
Smith, D. K., He, M., Zhang, C., & Zheng, J. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.006 · Cited by 34
“The proteolytic cleavage of mutant HTT generates short peptides with high aggregation potential (Scherzinger et al., 1997) and when localized to the nucleus these polyglutamine-rich aggregates become cytotoxic (Yang et al., 2002).”
Background
Asparagine and glutamine ladders promote cross-species prion conversion
Kurt, T. D., Aguilar‐Calvo, P., Jiang, L., Rodríguez, J. A., Alderson, N. B., Eisenberg, D. S., & Sigurdson, C. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.794107 · Cited by 32
“How do asparagine and glutamine residues lower the energy barrier for prion cross-seeding? Of relevance to Huntington’s disease, fibril assembly of the huntingtin protein is caused by expansion of poly(Q) tracts (44, 45).”
Background
Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
Bondulich, M. K., Jolinon, N., Osborne, G. F., Smith, E. J., Rattray, I., Neueder, A., Sathasivam, K., Ahmed, M., Ali, N. S., Benjamin, A. C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-14290-3 · Cited by 32
Self-citation
Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease
Niemelä, V., Landtblom, A., Nyholm, D., Kneider, M., Constantinescu, R., Paucar, M., Svenningsson, P., Abujrais, S., Burman, J., Shevchenko, G., et al. (2020) · Movement Disorders · doi:10.1002/mds.28391 · Cited by 31
Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G4C2 RNA in a cellular model
Frottin, F., Pérez‐Berlanga, M., Hartl, F. U., & Hipp, M. S. (2021) · eLife · doi:10.7554/elife.62718 · Cited by 33
Swimming against ALS: How to model disease in zebrafish for pathophysiological and behavioral studies
Oliveira, N. A. S., Pinho, B. R., & Oliveira, J. M. A. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105138 · Cited by 34
Animal models of Huntington's disease: implications in uncovering pathogenic mechanisms and developing therapies
Wang, L., & Qin, Z. (2006) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2006.00410.x · Cited by 32
Polyglutamine Fibrils: New Insights into Antiparallel β-Sheet Conformational Preference and Side Chain Structure
Punihaole, D., Workman, R. J., Hong, Z., Madura, J. D., & Asher, S. A. (2016) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5b11380 · Cited by 32
Recent advances in Huntingtonʼs disease
Gutekunst, C., Norflus, F., & Hersch, S. M. (2000) · Current Opinion in Neurology · doi:10.1097/00019052-200008000-00013 · Cited by 32
Amyloids and prions in plants: Facts and perspectives
Antonets, K., & Nizhnikov, A. (2017) · Prion · doi:10.1080/19336896.2017.1377875 · Cited by 28
Molecular investigation of TBP allele length: a SCA17 cellular model and population study.
Reid, S., Rees, M., van Roon-Mom, W. V., Jones, A., MacDonald, M., Sutherland, G., During, M., Faull, R., Owen, M., Dragunow, M., et al. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00014-7 · Cited by 35
Transgenic mouse models of neurodegenerative disease caused by CAG/polyglutamine expansions
Bates, G. P., & Davies, S. W. (1997) · Molecular Medicine Today · doi:10.1016/s1357-4310(97)01142-8 · Cited by 32
Self-citation
An Intein-based Strategy for the Production of Tag-free Huntingtin Exon 1 Proteins Enables New Insights into the Polyglutamine Dependence of Httex1 Aggregation and Fibril Formation
Vieweg, S., Ansaloni, A., Wang, Z.-M., Warner, J. B., & Lashuel, H. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.713982 · Cited by 31
“Second, fusing these proteins to mutant Httex1 proteins has been shown to alter their aggregation properties and favors the formation of round particles or amorphous aggregates (27, 39, 41, 59).”
Background
Structure and Dynamics of RNA Repeat Expansions That Cause Huntington’s Disease and Myotonic Dystrophy Type 1
Chen, J. L., VanEtten, D. M., Fountain, M., Yildirim, I., & Disney, M. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00252 · Cited by 30
Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3
Johnson, S. L., Blount, J. R., Libohova, K., Ranxhi, B., Paulson, H. L., Tsou, W., & Todi, S. V. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104535 · Cited by 31
Emerging Role of NLRP3 Inflammasome/Pyroptosis in Huntington’s Disease
Paldino, E., & Fusco, F. R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158363 · Cited by 31
“One of the most described features of mutated protein is its capacity to accumulate and aggregate [4,5] forming the intranuclear and intracytoplasmic neuronal inclusions (NIIs) which are now considered a pathological hallmark of the disease [6–9].”
Background
[43] Detection of polyglutamine aggregation in mouse models
Davies, S. W., Sathasivam, K., Hobbs, C., Doherty, P., Mangiarini, L., Scherzinger, E., Wanker, E. E., & Bates, G. P. (1999) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(99)09045-x · Cited by 31
Self-citation
Comparative analysis of the cytotoxicity of homopolymeric amino acids
Oma, Y., Kino, Y., Sasagawa, N., & Ishiura, S. (2005) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2004.12.017 · Cited by 31
Transglutaminase and diseases of the central nervous system.
Hoffner, G., & Djian, P. (2005) · Frontiers in Bioscience · doi:10.2741/1764 · Cited by 33
Post-aggregation Oxidation of Mutant Huntingtin Controls the Interactions between Aggregates
Mitomi, Y., Nomura, T., Kurosawa, M., Nukina, N., & Furukawa, Y. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.387035 · Cited by 31
“If necessary, 50 Mbathocuproine disulfonate (BCS), a specific chelator for Cu(I) ions, was added before addition of HRV3C but had no effects on the cleavage reactions by HRV3C protease.”
BackgroundMethodInfluential
Huntingtin affinity for partners is not changed by polyglutamine length: aggregation itself triggers aberrant interactions
Davranche, A., Aviolat, H., Zeder‐Lutz, G., Busso, D., Altschuh, D., Trottier, Y., & Klein, F. A. C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr178 · Cited by 36
“This ‘structural toxic threshold’ model has emerged in the late 1990s to accommodate several other observations: (i) the fact that some antibodies display a stronger interaction with expanded polyQ, which could suggest that mutant polyQ adopts a specific conformation (15,16), (ii) the discovery that expanded polyQ for…”
α-Aminoisobutyric acid modified protected analogues of β-amyloid residue 17–20: a change from sheet to helix
Haldar, D., Drew, M. G. B., & Banerjee, A. (2006) · Tetrahedron · doi:10.1016/j.tet.2006.04.036 · Cited by 31
Interactions between homopolymeric amino acids (HPAAs)
Oma, Y., Kino, Y., Toriumi, K., Sasagawa, N., & Ishiura, S. (2007) · Protein Science · doi:10.1110/ps.072955307 · Cited by 31
“2005), and polyglutamine-containing peptides have also been shown to form such structures in vitro and in vivo (Scherzinger et al. 1997; Huang et al. 1998).”
Background
The glutamine-rich domain of the Drosophila GAGA factor is necessary for amyloid fibre formation in vitro , but not for chromatin remodelling 1 1Edited by M. Yaniv
Agianian, B., Leonard, K., Bonte, E. J., van der Zandt, H., Becker, P. B., & Tucker, P. A. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.2355 · Cited by 31
Development of novel bioassays to detect soluble and aggregated Huntingtin proteins on three technology platforms
Landles, C., Milton, R. E., Jean, A., McLarnon, S., McAteer, S. J., Taxy, B. A., Osborne, G. F., Zhang, C., Duan, W., Howland, D., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcaa231 · Cited by 28
“The MW8-MW1 antibody pairing failed to provide an assay on all three platforms, consistent with the epitope for MW1 being lost during the aggregation process due to the formation of the cross-bsheet structure between glutamine tracts (Scherzinger et al., 1997).”
BackgroundMethodSelf-citation
Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
Herrmann, F., Heßmann, M., Schaertl, S., Berg-Rosseburg, K., Brown, C. J., Bursow, G., Chiki, A., Ebneth, A., Gehrmann, M., Hoeschen, N., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-97334-z · Cited by 30
Systematic Uncovering of Multiple Pathways Underlying the Pathology of Huntington Disease by an Acid-cleavable Isotope-coded Affinity Tag Approach
Chiang, M., Juo, C., Chang, H., Chen, H., Yi, E. C., & Chern, Y. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m600356-mcp200 · Cited by 30
“This protocol was adopted from earlier studies using the same mouse model of HD at similar disease stages (32) or cell models with large aggregates (19).”
Method
Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells
Büning, S., Sharma, A. A., Vachharajani, S., Newcombe, E. A., Ormsby, A. R., Gao, M., Gnutt, D., Vöpel, T., Hatters, D. M., & Ebbinghaus, S. (2017) · Physical Chemistry Chemical Physics · doi:10.1039/c6cp08167c · Cited by 30
The fatal attraction of polyglutamine‐containing proteins
Hackam, A. S., Wellington, C. L., & Hayden, M. R. (1998) · Clinical Genetics · doi:10.1111/j.1399-0004.1998.tb02687.x · Cited by 30
Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicityPreprint
Strödicke, M., Bounab, Y., Strempel, N. U., Klockmeier, K., Yigit, S., Friedrich, R. P., Chaurasia, G., Li, S., Hesse, F., Riechers, S., et al. (2015) · Genome Research · doi:10.1101/gr.182444.114 · Cited by 30
Self-citation
Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease
Lupton, C. J., Steer, D. L., Wintrode, P. L., Bottomley, S., Hughes, V. A., & Ellisdon, A. M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.659532 · Cited by 29
Excitotoxicity in Huntington disease
Raymond, L. A. (2003) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(03)00054-9 · Cited by 31
Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model
Lee, J., Kawaguchi, Y., Li, M., Kapur, M., Choi, S. J., Kim, H.-J., Park, S.-Y., Zhu, H., & Yao, T. (2015) · Neurodegenerative Diseases · doi:10.1159/000437208 · Cited by 30
Emerging chemotherapeutic strategies for Huntington’s disease
Ryu, H., & Ferrante, R. J. (2005) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.10.2.345 · Cited by 30
“Mutant huntingtin undergoes proteolytic processing, in part by the pro-apoptotic enzyme caspase-3, to release an N-terminal fragment containing the polyglutamine tract [98].”
Background
Molecular Pathogenesis of Spinocerebellar Ataxia Type 1 Disease
Kang, S., & Hong, S. (2009) · Molecules and Cells · doi:10.1007/s10059-009-0095-y · Cited by 31
Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions
Horwich, A. L. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200216781 · Cited by 30
The proteome of neurofilament-containing protein aggregates in blood
Adiutori, R., Aarum, J., Zubiri, I., Bremang, M., Jung, S., Sheer, D., Pike, I., & Malaspina, A. (2018) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2018.04.010 · Cited by 26
Rac1 Activity Is Modulated by Huntingtin and Dysregulated in Models of Huntington’s Disease
Tousley, A. R., Iuliano, M., Weisman, E., Sapp, E., Zhang, N., Vodička, P., Alexander, J. S., Aviolat, H., Gatune, L. W., Reeves, P., et al. (2018) · Journal of Huntington s Disease · doi:10.3233/jhd-180311 · Cited by 28
“Control GST protein was expressed from pGEX6P-1-FLAG-tag, a gift from Erich Wanker [45]. pGEX-2T-Rac1-wt was a gift from Gary Bokoch (Addgene plasmid # 12977).”
Method
Antibody-based therapies for Huntington’s disease: current status and future directions
Denis, H. L., David, L. S., & Cicchetti, F. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104569 · Cited by 33

Authors: Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E.
Affiliations: Max Planck Institute for Molecular Genetics (DE)
University College London (GB)
Guy's Hospital (GB)
Corresponding author: Wanker, Erich E
ORCID: Bates, Gillian P
Wanker, Erich E
Venue: Cell
Publisher: Elsevier BV
Published: 1997-08
Volume: 90
Issue: 3
Pages: 549-558
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(00)80514-0
OpenAlex: W2079250951
Cited by: 1,291
References: 42
Citations by year: 2026: 17 · 2025: 31 · 2024: 23 · 2023: 23 · 2022: 24 · 2021: 37 · 2020: 55 · 2019: 44 · 2018: 49 · 2017: 43 · 2016: 34 · 2015: 32 · 2014: 43 · 2013: 38 · 2012: 52
FWCI: 25.86
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 5829 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: Huntington's disease, polyglutamine expansion, huntingtin, protein aggregation, amyloid-like aggregates, proteolytic cleavage, GST fusion protein, neurodegeneration, transgenic mouse model, fibril morphology, amyloid-beta
MeSH terms: Huntingtin Protein, Amino Acid Sequence, Amyloid, Animals, Base Sequence, Brain, Cell Nucleus, Exons, Glutathione Transferase, Humans, Huntington Disease, Kidney, Mice, Transgenic, Molecular Sequence Data, Nerve Tissue Proteins, Nuclear Proteins, Recombinant Fusion Proteins, Polymerase Chain Reaction, DNA Primers, Macromolecular Substances, Mice

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Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo

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