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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Self-citation
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Background
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“Perutz has suggested that long stretches of polyglutamines may form hydrogen bonds to other extended stretches of polyglutamines in an antiparallel fashion (‘polar zippers’, 28) forming an aggregation of the protein in a noncovalent fashion (34, 41).”
Background
Causative Links between Protein Aggregation and Oxidative Stress: A Review
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Background
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Inhibiting transthyretin conformational changes that lead to amyloid fibril formation
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“As aggregated proteins can be seen in the stacking gel on western blots (20,21), we examined the aggregation of the HD exon 1 protein in R6/2 mice by western blotting.”
Method
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Functional insights from the distribution and role of homopeptide repeat-containing proteinsPreprint
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“Nine poly-Q-linked diseases have been identified, and the proteins believed to be responsible for the disease contain expanded poly-Q tracts that have been shown to possess an enhanced tendency to aggregate and form fibrils both in vitro and in vivo (Scherzinger et al. 1997; Skinner et al. 1997; Becher et al. 1998; Ho…”
Background
Cryo-EM structure of a neuronal functional amyloid implicated in memory persistence in Drosophila
Hervás, R., Rau, M., Park, Y., Zhang, W., Murzin, A. G., Fitzpatrick, J. A. J., Scheres, S. H. W., & Si, K. (2020) · Science · doi:10.1126/science.aba3526 · Cited by 194
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Background
Cytosolic Protein Vms1 Links Ribosome Quality Control to Mitochondrial and Cellular Homeostasis
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“Scherzinger et al. (1997) demonstrated that huntingtin polygln aggregation is a selfdriven process that occurs in a concentration-and repeat length–dependent manner and results in the formation of amyloid-like insoluble fibrils.”
Background
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“In studies of polyglutamine disorders, it has been demonstrated that high molecular weight aggregates of mutant huntingtin are retained by filtration through cellulose acetate (Scherzinger et al., 1997).”
BackgroundMethodInfluential
The molecular genetics of Huntington disease — a history
Bates, G. P. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1686 · Cited by 201
“Three years later it was shown that the protein encoded by exon 1 of the HD gene, which contains polyglutamine repeats in the pathogenic range, could spontaneously aggregate into amyloid fibrils in vitro”
Self-citation
Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy
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Huntingtin Bodies Sequester Vesicle-Associated Proteins by a Polyproline-Dependent Interaction
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BackgroundInfluentialSelf-citation
Inhibition of Polyglutamine Protein Aggregation and Cell Death by Novel Peptides Identified by Phage Display Screening
Nagai, Y., Tucker, T. J., Ren, H., Kenan, D. J., Henderson, B. S., Keene, J. D., Strittmatter, W. J., & Burke, J. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.14.10437 · Cited by 186
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“Human PrLDs possess an amino acid composition similar to yeast prion domains, which are LCDs enriched in glycine and polar, uncharged amino acids including glutamine, asparagine, tyrosine and serine (Alberti et al., 2009; Harrison and Shorter, 2017; Kim et al., 2013; March et al., 2016; Shorter and Lindquist, 2005).”
BackgroundInfluential
Effects of in vivo conditions on amyloid aggregation
Owen, M. C., Gnutt, D., Gao, M., Wärmländer, S. K. T. S., Jarvet, J., Gräslund, A., Winter, R., Ebbinghaus, S., & Strodel, B. (2019) · Chemical Society Reviews · doi:10.1039/c8cs00034d · Cited by 181
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“…band at 150–180 kDa (Miyashita et al.,tamine protein; aggregation may be driven through polar 1997; Wellington et al., 1998).zippers (Perutz, 1995; Scherzinger et al., 1997) and stabiBecause of the strong correlation between the levelslized by the action of transglutaminases (Igarashi et al., of…”
Background
The Cellular and Subcellular Localization of Huntingtin-Associated Protein 1 (HAP1): Comparison with Huntingtin in Rat and Human
Gutekunst, C., Li, S.-H., Yi, H. L., Ferrante, R. J., Li, X., & Hersch, S. M. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-19-07674.1998 · Cited by 181
“Recent studies have shown that N-terminal fragments of mutant huntingtin can form aggregates (Davies et al., 1997; DiFiglia et al., 1997; Scherzinger et al., 1997) that might play a role in cell injury.”
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Subtype‐Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin
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PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival
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Method
Untitled work
(1999) · doi:10.1002/1531-8249(199902)45:2
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Pathological consequences of VCP mutations on human striated muscle
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“GST-, MBP- and His-tagged fusion proteins were expressed in Escherichia coli and purified on affinity columns as described previously (Scherzinger et al., 1997) and according to manufacturer’s instructions (NEB, USA; Qiagen, Germany).”
Self-citation
Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease
Labbadia, J. P., Cunliffe, H. E., Weiss, A., Katsyuba, E., Sathasivam, K., Seredenina, T. S., Woodman, B., Moussaoui, S. M., Frentzel, S., Luthi‐Carter, R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57413 · Cited by 172
Self-citation
Disulfide Bond Mediates Aggregation, Toxicity, and Ubiquitylation of Familial Amyotrophic Lateral Sclerosis-linked Mutant SOD1
Niwa, J., Yamada, S., Ishigaki, S., Sone, J., Takahashi, M., Katsuno, M., Tanaka, F., Doyu, M., & Sobue, G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704465200 · Cited by 172
Physical Chemistry of Polyglutamine: Intriguing Tales of a Monotonous Sequence
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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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