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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Background
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Background
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Background
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Background
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Background
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BackgroundMethodInfluentialSelf-citation
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Background
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Autophagy, inflammation and neurodegenerative disease
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Background
Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: Interactions between neurons and astrocytes
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“Intra-cellular aggregates of mutant HTT are found in both the cytoplasm and nucleus [59].”
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A protein quality control pathway regulated by linear ubiquitination
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“This approach is based on the insolubility of Htt aggregates in SDS and their selective retention on a cellulose acetate membrane, whereas SDS-soluble proteins are filtered through the membrane (Scherzinger et al , 1997).”
Cross-Seeding Fibrillation of Q/N-Rich Proteins Offers New Pathomechanism of Polyglutamine Diseases
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“Htt exon I with 42 glutamines (Htt42Q) was prepared as a fusion protein with GST (GSTHtt42Q) (Scherzinger et al., 1997).”
BackgroundMethod
Simultaneous Measurement of Amyloid Fibril Formation by Dynamic Light Scattering and Fluorescence Reveals Complex Aggregation Kinetics
Streets, A., Sourigues, Y., Kopito, R. R., Melki, R., & Quake, S. R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054541 · Cited by 90
A Conditional Pan-NeuronalDrosophilaModel of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes
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“…of function mediated by the polyQ expansion, but the role of NIIs in the pathogenesis of the disease remains unclear: toxic (Davies et al., 1997; Scherzinger et al., 1997, 1999; Skinner et al., 1997; Becher et al., 1998; Gusella and MacDonald, 2000), nontoxic (Holmberg et al., 1998; Klement et…”
Background
Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1
Hyrskyluoto, A., Bruelle, C., Lundh, S. H., Do, H. T., Kivinen, J., Rappou, E., Reijonen, S., Waltimo, T., Petersén, Å., Lindholm, D., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu317 · Cited by 90
Mutant protein in Huntington disease is resistant to proteolysis in affected brain
Dyer, R. B., & McMurray, C. T. (2001) · Nature Genetics · doi:10.1038/ng745 · Cited by 92
“N-terminal fragments are known to be poorly solubl”
Background
Formic Acid Dissolves Aggregates of an N-Terminal Huntingtin Fragment Containing an Expanded Polyglutamine Tract: Applying to Quantification of Protein Components of the Aggregates
Hazeki, N., Tukamoto, T., Goto, J., & Kanazawa, I. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3682 · Cited by 91
Serine Phosphorylation Suppresses Huntingtin Amyloid Accumulation by Altering Protein Aggregation Properties
Mishra, R. K., Hoop, C. L., Kodali, R. B., Sahoo, B., van der Wel, P. C. A., & Wetzel, R. B. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2012.09.011 · Cited by 90
Pathogenic and Non-pathogenic Polyglutamine Tracts Have Similar Structural Properties: Towards a Length-dependent Toxicity Gradient
Klein, F. A. C., Pastore, A., Masino, L., Zeder‐Lutz, G., Nierengarten, H., Oulad‐Abdelghani, M., Altschuh, D., Mandel, J., & Trottier, Y. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.028 · Cited by 91
Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders
Carra, S., Rusmini, P., Crippa, V., Giorgetti, E., Boncoraglio, A., Cristofani, R., Naujock, M., Meister, M., Minoia, M., Kampinga, H. H., et al. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0409 · Cited by 90
“As previously mentioned, many neurodegenerative diseases, including AD, polyQ diseases and PD, are characterized by the accumulation of fibrillar proteinaceous aggregates in specific neuronal types [111–117].”
Background
The Role of Interruptions in polyQ in the Pathology of SCA1
Menon, R. P., Nethisinghe, S., Faggiano, S., Vannocci, T., Rezaei, H., Pemble, S. E., Sweeney, M. G., Wood, N. W., Davis, M. B., Pastore, A., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003648 · Cited by 87
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BackgroundMethod
Abnormal Properties of Prion Protein with Insertional Mutations in Different Cell Types
Priola, S. A., & Chesebro, B. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11980 · Cited by 88
Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons
Goffredo, D., Rigamonti, D., Tartari, M., Micheli, A. D., Verderio, C., Matteoli, M., Zuccato, C., & Cattaneo, E. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200353200 · Cited by 86
Deciphering the Structure, Growth and Assembly of Amyloid-Like Fibrils Using High-Speed Atomic Force Microscopy
Milhiet, P., Yamamoto, D., Berthoumieu, O., Dosset, P., Grimellec, C. L., Verdier, J., Marchal, S., & Ando, T. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013240 · Cited by 89
“That is the case for insulin [5], the SH3 domain of bovine PI3K [6], myoglobin [7] and prion proteins [8]; ii) the ‘‘natively disordered’’ model, composed of proteins or peptides whose native structure was mainly disordered such as polyglutamine proteins [9], huntingtin [10], ataxins, yeast prions or the amyloid beta…”
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Is the ubiquitin-proteasome system impaired in Huntington’s disease?
Ortega, Z., Dı́az-Hernández, M., & Lucas, J. J. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7222-8 · Cited by 86
Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice
Schilling, G., Savonenko, A. V., Coonfield, M. L., Morton, J. L., Vorovich, E. B., Gale, A., Neslon, C., Chan, N., Eaton, M., Fromholt, D., et al. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.01.003 · Cited by 85
Intraneuronal Aggregate Formation and Cell Death after Viral Expression of Expanded Polyglutamine Tracts in the Adult Rat Brain
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“…with long polyQ repeats results in the time-dependent formation of cytoplasmic and nuclear aggregates of fibrillar structures (Onodera et al., 1997; Scherzinger et al., 1997; Martindale et al., 1998) that may trigger cell toxicity via inappropriate apoptotic cell death (Goldberg et al., 1996;…”
Background
Detection of internal repeats: how common are they?
Heringa, J. (1998) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(98)80068-7 · Cited by 83
Evolution of the Primate Androgen Receptor: A Structural Basis for Disease
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“The cells were also incubated with 150mCi of [32P]orthophosphate for 2 h at 37°C and harvested in RIPA buffer (Kemppainen et al. 1992), and the AR was immunoprecipitated using antipeptide antibody AR52 and analyzed on 9 or 12% acrylamide gels containing SDS.”
BackgroundInfluential
Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases
Lim, J. L., Wilhelmus, M. M. M., de Vries, H. E., Drukarch, B., Hoozemans, J. J. M., & van Horssen, J. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1338-z · Cited by 84
Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle
Lotz, G. P., Legleiter, J. A., Aron, R., Sontag, E. M., Huang, S., Ng, C.-P., Glabe, C. G., Thompson, L. M., & Muchowski, P. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.160218 · Cited by 82
Activation of MLK2-mediated Signaling Cascades by Polyglutamine-expanded Huntingtin
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Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
Peng, W., Minakaki, G., Nguyen, M., & Krainc, D. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00742-3 · Cited by 79
m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration
Sun, Y., Dai, H., Dai, X., Yin, J., Cui, Y., Liu, X., Gonzalez, G. M., Yuan, J. J., Tang, F., Wang, N., et al. (2023) · Nature · doi:10.1038/s41586-023-06701-5 · Cited by 89
“…been proposed for neurological diseases elicited by repeat expansions; these include neurotoxicity arising from formation of neuronal intranuclear inclusions and amyloid-like aggregates of proteins translated from repeat RNAs 3,4 , and the ensuing impairment of the ubiquitin–proteasome system 11 .”
Influential
Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease
Richards, P., Didszun, C., Campesan, S., Simpson, A., Horley, B., Young, K. W., Glynn, P., Cain, K., Kyriacou, C. P., Giorgini, F., et al. (2011) · Cell Death & Differentiation · doi:10.1038/cdd.2010.127 · Cited by 82
“The expansion of this polyQ region beyond a critical threshold of B35 glutamines leads to formation of insoluble intranuclear and cytoplasmic amyloid fibers resulting from self-association of mutant htt.(2) Mutant htt-containing aggregates have been identified in the brains of HD patients,(3) as well as in mice expres…”
Background
Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation
Robertson, A. L., Headey, S. J., Saunders, H. M., Ecroyd, H. W., Scanlon, M. J., Carver, J. A., & Bottomley, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914773107 · Cited by 82
“So we tested whether SpAcQ52 incubated with αB-c forms SDS-insoluble aggregates by using a membrane filter-trap assay (29).”
Method
Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion
Brandstaetter, H., Kishi‐Itakura, C., Tumbarello, D. A., Manstein, D. J., & Buß, F. (2014) · Autophagy · doi:10.4161/15548627.2014.984272 · Cited by 82
“autophagy phenotype affects the autophagy-dependent clearance of HTT/huntingtin-polyQ protein aggregates.(17) We analyzed whether loss of MYO1C expression has an effect on clearance of HTT protein containing a pathological poly Q expansion, which leads to misfolding and aggregation.”
Background
Analysis of repetitive amino acid motifs reveals the essential features of spider dragline silk proteins
Malay, A. D., Arakawa, K., & Numata, K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0183397 · Cited by 82
Polyglutamine pathogenesis
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“(a) In vitro studies The study of Scherzinger et al. (1997) was the ¢rst demonstration of the inherent ability of polyglutaminecontaining protein to aggregate.”
Background
Truncated Forms of the Androgen Receptor are Associated with Polyglutamine Expansion in X-Linked Spinal and Bulbar Muscular Atrophy
Butler, R. K., Leigh, P. N., McPhaul, M. J., & Gallo, J. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.1.121 · Cited by 82
“R ecently, huntingtin-containing neuronal intranuclear inclusions has been described in transgenic mice expressing exon 1 of the huntingtin gene (43,44).”
Background
Ubiquitin, Autophagy and Neurodegenerative Diseases
Watanabe, Y., Taguchi, K., & Tanaka, M. (2020) · Cells · doi:10.3390/cells9092022 · Cited by 86
“Cleaved N-terminal fragments with an expanded polyQ tract are released and form fibrillary aggregates or inclusion bodies [61].”
Background
Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation
Malinovska, L., Palm, S., Gibson, K. H., Verbavatz, J., & Alberti, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504459112 · Cited by 84
“This is surprising, because polyQ stretches above this threshold have been linked to fatal diseases in humans (21).”
Background
Polyglutamine Expansion Induces a Protein-damaging Stress Connecting Heat Shock Protein 70 to the JNK Pathway
Mérienne, K., Helmlinger, D., Perkin, G. R., Devys, D., & Trottier, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212049200 · Cited by 81
Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases
de Pril, R., Fischer, D. F., Roos, R. A. C., & van Leeuwen, F. W. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.09.006 · Cited by 84
Neurodegenerative diseases: Lessons from genome‐wide screens in small model organisms
van Ham, T. J., Breitling, R., Swertz, M. A., & Nollen, E. A. A. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900051 · Cited by 82
“…cerevisiae, the nematode worm enorhabditis elegans and the fruit fly Drosophila melanogaster—have been used to del these diseases and high-throughput genetic screens using these models have to the identification of a large number of genes that modify aggregation and icity of the disease proteins.”
Background
From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington'sdisease
Davies, S. W., Turmaine, M., Cozens, B. A., Raza, A. S., Mahal, A., Mangiarini, L., & Bates, G. P. (1999) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1999.0448 · Cited by 81
“Experiments in vitro (see Hollenbach et al., this issue) have further shown that the transgene-encoded huntingtin protein assembles into ¢brils that show birefringence when stained with Congo red, and is indicative of a b-pleated sheet structure (Scherzinger et al. 1997).”
InfluentialSelf-citation
Molecular and structural architecture of polyQ aggregates in yeast
Gruber, A., Hornburg, D., Antonin, M., Krahmer, N., Collado, J., Schaffer, M., Zubaite, G., Lüchtenborg, C., Sachsenheimer, T., Brügger, B., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717978115 · Cited by 75
“HD is caused by the expansion of a polyQ repeat in the N-terminal exon of huntingtin (HttEx1), which leads to protein aggregation and cell death (2, 10, 11).”
Background
The Effect of (−)-Epigallo-catechin-(3)-gallate on Amyloidogenic Proteins Suggests a Common Mechanism
Andrich, K., & Bieschke, J. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-18365-7_7 · Cited by 83
“1986), Huntingtin protein (Htt) in Huntington’s disease (HD) (Trottier et al. 1995; Scherzinger et al. 1997), alpha-Synuclein (α-Syn) in Parkinson’s disease (PD) (Takeda et al.”
Background
Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease
Dı́az-Hernández, M., Torres-Peraza, J. F., Salvatori-Abarca, A., Morán, M. A., Gómez‐Ramos, P., Alberch, J., & Lucas, J. J. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3183-05.2005 · Cited by 80
“Initially, they were postulated to be the trigger for neurodegeneration, because both aggregation and pathogenicity are caused by the same polyQ length threshold (Scherzinger et al., 1997).”
Background
A novel therapeutic strategy for polyglutamine diseases by stabilizing aggregation-prone proteins with small molecules
Tanaka, M., Machida, Y., & Nukina, N. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0632-2 · Cited by 79
“Cleaved fragments such as truncated N-terminal huntingtin show a virtually unordered structure [5] whereas”
Background
Huntingtin Aggregation Kinetics and Their Pathological Role in aDrosophilaHuntington’s Disease Model
Weiss, K. R., Kimura, Y., Lee, W.-C. M., & Littleton, J. T. (2011) · Genetics · doi:10.1534/genetics.111.133710 · Cited by 80
“Similar to other polyQ-repeat neurological disorders, abnormal protein conformation(s) secondary to polyQ expansion are central to HD pathogenesis (PERSICHETTI et al. 1999; SCHERZINGER et al. 1997).”
Background
Towards a Structural Understanding of the Fibrillization Pathway in Machado-Joseph's Disease: Trapping Early Oligomers of Non-expanded Ataxin-3
Gales, L., Cortes, L., Almeida, C. M., Melo, C. V., Costa, M. D. C., Maciel, P., Clarke, D. T., Damas, A. M., & Macedo‐Ribeiro, S. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.08.061 · Cited by 80
“The amyloid nature of these polyglutamine insoluble structures has been demonstrated by numerous experiments in vitro and in vivo.(7,10) Furthermore, poly(Q) aggregates are recognized by “pan-amyloid” antibodies able to associate with generic amyloid epitopes in fibrils formed from a diverse number of proteins.”
Background
The Induction Levels of Heat Shock Protein 70 Differentiate the Vulnerabilities to Mutant Huntingtin among Neuronal Subtypes
Tagawa, K., Marubuchi, S., Qi, M., Enokido, Y., Tamura, T., Inagaki, R., Murata, M., Kanazawa, I., Wanker, E. E., & Okazawa, H. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4522-06.2007 · Cited by 79
Self-citation

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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