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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MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth
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Overexpression of F0F1-ATP synthase α suppresses mutant huntingtin aggregation and toxicity in vitro
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“The expansion of the CAG repeat in htt results in polyQ tract in the extreme NH2 terminus of the protein that destabilizes the protein, leading to the formation of SDS-insoluble protein aggregates also known as inclusion bodies (IBs) in vitro and in vivo [2,3].”
Background
Interaction of selected divalent metal ions with human ataxin-3 Q36
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The Ins and Outs of a Polyglutamine Neurodegenerative Disease: Spinocerebellar Ataxia Type 1 (SCA1)
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Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
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Measurement of Chaperone-Mediated Effects on Polyglutamine Protein Aggregation by the Filter Trap Assay
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Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease
Zhou, Y., Peskett, T. R., Landles, C., Warner, J. B., Sathasivam, K., Smith, E. J., Chen, S., Wetzel, R. B., Lashuel, H. A., Bates, G. P., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01172-z · Cited by 21
“The exon 1 HTT protein is particularly aggregation-prone [68].”
BackgroundSelf-citation
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“The flanking sequences have been shown to play a structural role in polyQ sequences, both in synthetic and natural peptides, and both in monomeric or aggregate form [4,16,17,19].”
Proteome changes in the aging Drosophila melanogaster head
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“2 Controversy over the role of aggregates The aggregate theory was strongly supported by in vitro studies showing that the kinetics of polyglutamine tract self-aggregation is accelerated with lengthening of the glutamine repeat size [13], a correlation that mirrored the genotype–phenotype relationships in these diseas…”
Result
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“In vitro analysis using GST-fused ex-polyQ and several cellular models clearly demonstrated that polypeptides containing long polyQ aggregate easily when surrounding protein portions become short (Ikeda et al., 1996; Scherzinger et al., 1997).”
Background
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Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice
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“The underlying cause of HD is an elongated CAG trinucleotide repeat expansion in exon 1 of the HTT gene, resulting in the formation of mutant HTT protein with an abnormally long poly-glutamine tail that exhibits a propensity to aggregate 3,4 .”
Purification of Polyglutamine Proteins1
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Organelle asymmetry for proper fitness, function, and fate
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“Because aggresome formation has been linked to a number of severe human pathologies, including cystic fibrosis (Johnston et al. 1998) and Huntingtin's disease (Scherzinger et al. 1997) , the mode of aggresome inheritance has been the topic of a number of studies.”
Effect of Pesticides on the Aggregation of Mutant Huntingtin Protein
Deshmukh, R. S., Chaudhary, R. K., & Roy, I. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8252-2 · Cited by 20
“The expressed protein was purified using glutathione–agarose matrix [57].”
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Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans
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Prefibrillar huntingtin oligomers isolated from HD brain potently seed amyloid formation
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Nanoimaging for prion related diseases
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Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity
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Atomic Force Microscopy Analysis of the Huntington Protein Nanofibril Formation
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“Over time, these insoluble aggregates deposit especially in the striatum and subsequently selectively kill neurons [9].”
BackgroundInfluential
Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease
Helabad, M. B., Matlahov, I., Kumar, R., Daldrop, J. O., Jain, G., Weingarth, M. H., van der Wel, P. C. A., & Miettinen, M. S. (2024) · Nature Communications · doi:10.1038/s41467-024-55062-8 · Cited by 19
A clinical study and future prospects for bioactive compounds and semi-synthetic molecules in the therapies for Huntington's disease
Islam, M. R., Jony, M. H., Thufa, G. K., Akash, S., Dhar, P. S., Rahman, M. M., Afroz, T., Ahmed, M., Hemeg, H. A., Rauf, A., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03604-4 · Cited by 20
“In vitro and in vivo , the enlarged proteins undergo a conformational change that results in the development of protein aggregates resistant to sodium dodecyl sulphate (SDS) [67, 68].”
Photocontrol of the β-Hairpin Polypeptide Structure through an Optimized Azobenzene-Based Amino Acid Analogue
Parlato, R., Volarić, J., Lasorsa, A., Helabad, M. B., Kobauri, P., Jain, G., Miettinen, M. S., Feringa, B. L., Szymański, W., & van der Wel, P. C. A. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c11155 · Cited by 19
Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic cell death
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A network of genes connects polyglutamine toxicity to ploidy control in yeast
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Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation
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“Because of its similarity to amyloid-forming polyQ stretches in huntingtin (14) and the androgen receptor (15), the main Q/H-rich stretch (residues 23–53) was suspected to be key for Orb2 amyloid formation.”
Background
Structural Characterization of Apomyoglobin Self-Associated Species in Aqueous Buffer and Urea Solution
Chow, C., Kurt, N., Murphy, R. M., & Cavagnero, S. (2005) · Biophysical Journal · doi:10.1529/biophysj.105.070227 · Cited by 19
Epitope Mapping of Monoclonal Antibody 4C8 Recognizing the Protein Huntingtin
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Adenovirus-Mediated Silencing of Huntingtin Expression by shRNA
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Differential morphology and composition of inclusions in the R6/2 mouse and PC12 cell models of Huntington’s disease
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“studies of the structure of inclusions have dealt primarily with inclusions formed by biochemical methods or with inclusions isolated by chemical means such as tandem-aYnity chromatography and homogenization/ extraction (Diaz-Hernandez et al. 2004; Mukai et al. 2005; Scherzinger et al. 1997).”
Background
CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci.
Frontali, M., Novelletto, A., Annesi, G., & Jodice, C. (1999) · Philosophical transactions of the Royal Society of London. Series B, Biological sciences · doi:10.1098/rstb.1999.0464 · Cited by 20
“…been shown, both in vivo and in vitro, that expanded polyglutamine stretches lead to the formation of intranuclear inclusions containing insoluble ubiquitinated aggregates of the protein (see, for example, Davis et al. 1997; Di Figlia et al. 1997; Paulson et al. 1997; Scherzinger et al. 1997).”
Background
DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation
Saad, S., Swigut, T., Tabatabaee, S., Lalgudi, P. V., Jarosz, D. F., & Wysocka, J. (2025) · Cell · doi:10.1016/j.cell.2025.03.031 · Cited by 17
“HTT-polyQ forms amyloid aggregates, deﬁned by strong resistance to SDS. 49–51 We performed a ﬁlter trap assay 52 to assess whether DBD fusion can render these aggregates SDS soluble.”
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Putting Huntingtin “Aggregation” in View with Windows into the Cellular Milieu
Hatters, D. M. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611212220013 · Cited by 18
“This is supported by the observation that Htt becomes SDS insoluble in cells when inclusion bodies form, which is a property of Htt fibrils formed in vitro [79-80].”
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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