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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BackgroundSelf-citation
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Method
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Method
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Method
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Rousseau, E., Dehay, B., Ben-Haı̈em, L., Trottier, Y., Morange, M., & Bertolotti, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403015101 · Cited by 51
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Background
Neuronal Intranuclear Inclusions in Polyglutamine Diseases
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Background
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Background
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BackgroundMethodResultInfluential
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“One of the major pathological features found in HD neurons is the presence of detergent-insoluble ubiquitinated inclusions composed of poly(Q)-expanded mutant htt (mhtt) (Davies et al., 1997; Scherzinger et al., 1997).”
Background
One‐Pot Semisynthesis of Exon 1 of the Huntingtin Protein: New Tools for Elucidating the Role of Posttranslational Modifications in the Pathogenesis of Huntington’s Disease
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Huntingtin processing in pathogenesis of Huntington disease.
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Background
Directed PCR-free engineering of highly repetitive DNA sequences
Scior, A., Preißler, S., Koch, M., & Deuerling, E. (2011) · BMC Biotechnology · doi:10.1186/1472-6750-11-87 · Cited by 46
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MethodInfluential
Spinocerebellar ataxia type 1
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Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models
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Background
Polyglutamine expansion diseases: More than simple repeats
Silva, A., de Almeida, A. V., & Macedo‐Ribeiro, S. (2017) · Journal of Structural Biology · doi:10.1016/j.jsb.2017.09.006 · Cited by 45
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“The key role of QN-rich CBRs in amyloid formation was initially demonstrated on the human poly-Q expanded Huntingtin protein [39] and further deepened by the data obtained on the yeast amyloid-forming proteins [40].”
Background
Meso scale discovery-based assays for the detection of aggregated huntingtin
Reindl, W., Baldo, B., Schulz, J., Janack, I., Lindner, I., Kleinschmidt, M. A., Sedaghat, Y., Thiede, C., Tillack, K., Schmidt, C., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0213521 · Cited by 44
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Cerebellar Allografts Survive and Transiently Alleviate Ataxia in a Transgenic Model of Spinocerebellar Ataxia Type-1
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“Recently, filtration methods have been used to quantify the products of protein aggregation reactions (12,13).”
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Atomic force microscopy analysis of the Huntington protein nanofibril formation
Dahlgren, P. R., Karymov, M. A., Bankston, J. R., Holden, T., Thumfort, P. P., Ingram, V. M., & Lyubchenko, Y. L. (2005) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2004.11.004 · Cited by 44
Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis
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Pathological mechanisms in Huntington's disease and other polyglutamine expansion diseases
Lunkes, A., Trottier, Y., & Mandel, J. (1998) · Essays in Biochemistry · doi:10.1042/bse0330149 · Cited by 44
“[30] found that a short truncated huntingtin with 51 glutamines may form amyloid-like aggregates in vitro, with a fibrillar morphology similar to those observed in Alzheimer’s disease and prion diseases [28].”
Result
Characterization of two isoforms of a human DnaJ homologue, HSJ2
Hanai, R., & Mashima, K. (2003) · Molecular Biology Reports · doi:10.1023/a:1024916223616 · Cited by 43
GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway
Hyrskyluoto, A., Reijonen, S., Kivinen, J., Lindholm, D., & Korhonen, L. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.08.020 · Cited by 43
Repeat-Associated Non-AUG Translation and Its Impact in Neurodegenerative Disease
Kearse, M. G., & Todd, P. K. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0292-z · Cited by 43
“the native functions of the protein [22–26].”
Self-assembly of Mutant Huntingtin Exon-1 Fragments into Large Complex Fibrillar Structures Involves Nucleated Branching
Wagner, A. S., Politi, A. Z., Ast, A., Bravo‐Rodriguez, K., Baum, K., Buntru, A., Strempel, N. U., Brusendorf, L., Hänig, C., Boeddrich, A., et al. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.03.017 · Cited by 43
Self-citation
Mutational analysis of designed peptides that undergo structural transition from α helix to β sheet and amyloid fibril formation
Takahashi, Y., UENO, A., & Mihara, H. (2000) · Structure · doi:10.1016/s0969-2126(00)00183-0 · Cited by 43
“In addition, abnormal expansion of Gln repeats in proteins that were linked to several inherited neurodegenerative diseases [59,60] or fibril-forming ability of a glutamine-rich domain of a DNA-binding protein [61] have also been reported.”
Background
Misfolding of Proteins with a Polyglutamine Expansion Is Facilitated by Proteasomal Chaperones
Rousseau, E., Kojima, R., Hoffner, G., Djian, P., & Bertolotti, A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806256200 · Cited by 54
Structural studies on the mechanism of protein aggregation in age related neurodegenerative diseases
Eftekharzadeh, B., Hyman, B. T., & Wegmann, S. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.03.001 · Cited by 44
Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging Caenorhabditis elegans
Laine, R. F., Sinnige, T., Yu, K., Haack, A. J., Poudel, C., Gaida, P., Curry, N., Perni, M., Nollen, E. A. A., Dobson, C. M., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00354 · Cited by 38
Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms
Tao, M., PANDEY, N. K., Barnes, R., Han, S., & Langen, R. (2019) · Structure · doi:10.1016/j.str.2019.08.003 · Cited by 42
Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease
Greco, T. M., Secker, C., Ramos, E. S., Federspiel, J. D., Liu, J.-P., Perez, A. M., Al‐Ramahi, I., Cantle, J. P., Carroll, J. B., Botas, J., et al. (2022) · Cell Systems · doi:10.1016/j.cels.2022.01.005 · Cited by 42
Self-citation
The Type I Hsp40 Ydj1 Utilizes a Farnesyl Moiety and Zinc Finger-like Region to Suppress Prion Toxicity
Summers, D. W., Douglas, P. M., Ren, H.-Y., & Cyr, D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807369200 · Cited by 42
Differential hydrophobicity drives self-assembly in Huntington's disease
Burke, M. G., Woscholski, R., & Yaliraki, S. N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1936025100 · Cited by 42
Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?
Castorina, A., Szychlinska, M. A., Marzagalli, R., & Musumeci, G. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.158352 · Cited by 42
“…β -amyloid peptides and tau/phosphorylated tau proteins in Alzheimer’s disease (AD), α -synuclein in Parkinson’s disease (PD), superoxide dismutase (SOD) in amyotrophic lateral sclerosis (ALS) (Durham et al., 1997), and mutant huntingtin in Huntington’s disease (HD) (Scherzinger et al., 1997).”
Background
Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease
Berggren, K. L., Chen, J., Fox, J. A., Miller, J., Dodds, L., Dugas, B., Vargas, L., Lothian, A., McAllum, E., Volitakis, I., et al. (2015) · Redox Biology · doi:10.1016/j.redox.2015.02.002 · Cited by 42
The Chaperone Grp78 in Protein Folding Disorders of the Nervous System
Moreno, J. A., & Tiffany‐Castiglioni, E. (2014) · Neurochemical Research · doi:10.1007/s11064-014-1405-0 · Cited by 41
Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity
Zhu, Y., Li, C. V., Tao, X., Brazill, J. M., Park, J., Diaz-Perez, Z., & Zhai, R. G. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904563116 · Cited by 40
“Here, we provide in vivo evidence that ThS amyloid-like Htt aggregates accumulates with age, consistent with the previous findings that β-structures are enriched during the process of misfolding and aggregation of polyQ proteins (39, 59).”
Result
Investigating the Structure of Neurotoxic Protein Aggregates Inside Cells
Bäuerlein, F. J. B., Fernández‐Busnadiego, R., & Baumeister, W. P. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.08.007 · Cited by 39
Small molecule drug discovery for Huntington's Disease
Fecke, W., Gianfriddo, M., Gaviraghi, G., Terstappen, G. C., & Heitz, F. (2009) · Drug Discovery Today · doi:10.1016/j.drudis.2009.02.006 · Cited by 43
“31 Scherzinger, E. et al. (1997) Huntingtin-encoded polyglutamine expansions form”
Background
Role of Protein Misfolding in DFNA9 Hearing Loss
Yao, J., Py, B. F., Zhu, H., Bao, J., & Yuan, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.106724 · Cited by 39
Rapid Detection of Protein Aggregates in the Brains of Alzheimer Patients and Transgenic Mouse Models of Amyloidosis
Xu, G., Gonzales, V., & Borchelt, D. R. (2002) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200207000-00010 · Cited by 37
“From studies of Huntington disease, an alternative approach to detecting aggregated proteins has emerged whereby tissue samples are filtered through cellulose acetate membranes (Scherzinger et al., 1997; Scherzinger et al., 1999).”
Background
The channel hypothesis of Huntington’s disease
Kagan, B. L., Hirakura, Y., Azimov, R., & Azimova, R. (2001) · Brain Research Bulletin · doi:10.1016/s0361-9230(01)00654-2 · Cited by 41
Analysis of gait abnormalities in huntington disease
Reynolds, N. C., Myklebust, J. B., Prieto, T. E., & Myklebust, B. M. (1999) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/s0003-9993(99)90308-8 · Cited by 41
Huntingtin is degraded to small fragments by calpain after ischemic injury☆
Kim, M., Roh, J., Yoon, B. W., Kang, L., Kim, Y. J., D, N. A. M., & DiFiglia, M. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00132-8 · Cited by 41
Inhibition of polyglutamine aggregate cytotoxicity by a structure‐based elongation inhibitor
Thakur, A. K., Yang, W., & Wetzel, R. B. (2004) · The FASEB Journal · doi:10.1096/fj.03-1238fje · Cited by 41
“PolyGln aggregates resemble amyloid fibrils in several critical features: (a) their being dominated by β-sheet structure; (b) their in vitro growth mechanism, which involves a nucleation-dependent assembly mechanism; (c) their protofibrillar substructure; and (d) their ability to be recognized by recently described “p…”
Background
Proteins with Intrinsically Disordered Domains Are Preferentially Recruited to Polyglutamine Aggregates
Wear, M. P., Kryndushkin, D. S., O’Meally, R. N., Sonnenberg, J. L., Cole, R. N., & Shewmaker, F. P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136362 · Cited by 38
Linear and extended: a common polyglutamine conformation recognized by the three antibodies MW1, 1C2 and 3B5H10
Klein, F. A. C., Zeder‐Lutz, G., Cousido-Siah, A., Mitschler, A., Katz, A., Eberling, P., Mandel, J., PODJARNY, A. D., & Trottier, Y. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt273 · Cited by 40
“This model was initially proposed based on differences observed between wildtype and mutant polyQ proteins: expanded polyQ was shown to be specifically recognized by the 1C2 antibody (9) and to perturb the interaction of a carrier protein with a partner (5); moreover, only expanded polyQ proteins were initially found…”
BackgroundMethod
Modeling Huntington׳s disease with patient-derived neurons
Mattis, V. B., & Svendsen, C. N. (2015) · Brain Research · doi:10.1016/j.brainres.2015.10.001 · Cited by 40
“These aggregates are well characterized in HD (Scherzinger et al., 1997), but normally at later stages of development.”
Background
Mutant huntingtin increases nuclear corepressor function and enhances ligand-dependent nuclear hormone receptor activation
Yohrling, G. J., Farrell, L. A., Hollenberg, A. N., & Cha, J.-H. J. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/s1044-7431(03)00032-0 · Cited by 40
The early cellular pathology of Huntington’s disease
Li, X.-J. (1999) · Molecular Neurobiology · doi:10.1007/bf02742437 · Cited by 31
“Huntingtin with a polyQ expansion in the pathological range (51 glutamines) can even form amyloid-like aggregates in vitro (49).”
Background

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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