Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo
Open accessAbstract
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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Mutant huntingtin has a propensity to aggregate in the nucleus and cytoplasm, in dendrites and dendritic spines, in human HD patients and animal models.
“Mutant huntingtin, however, has a propensity to aggregate in the nucleus and in the cytoplasm, which is reported both in human HD patients and in animal models, in dendrites as well as in dendritic spines (Di-Figlia et al., 1997;Scherzinger et al., 1997;Gutekunst et al., 1999;Lunkes et al., 2002).”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Scherzinger et al., 1997
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Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation
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“The inherent property of polyQ-containing proteins to self-aggregate has been well established (Perutz, 1999; Scherzinger et al., 1997), suggesting that Ac-Htt detected in the HMW fractions may exist, in part, as a self-associated oligomeric species.”
Sonication of proteins causes formation of aggregates that resemble amyloid
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“Amyloid fibrils and associated structures are generally very stable and resistant to resolubilization through various physical and chemical treatments, such as heat, reducing agents, and detergents (Glover et al. 1997; Scherzinger et al. 1997; Tanaka et al. 2002; Stefani and Dobson 2003).”
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“lysis buffer (SDS-buffer) (Scherzinger et al., 1997),”
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“Filter retardation assays were performed as described previousl”
MethodMolecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease
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“To detect small amounts of multimer in a quantifiable manner we used a membrane-trap assay that has previously been used to detect SDS-insoluble polyQ and Huntington oligomers as well as the oligomer-specific epitopes of Ab, Huntington, and asynuclein proteins (Kayed et al., 2003; Muchowski et al., 2002; Scherzinger e…”
Molecular mechanisms underlying nucleotide repeat expansion disorders
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Amyloid β-Protein Oligomerization
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Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration
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Protein aggregates in Huntington's disease
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“When the GST tag was proteolytically cleaved, aggregation of Htt-containing proteins occurred according to the length of the polyQ stretch (Scherzinger et al., 1997, 1999).”
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“exon 1 construct have revealed that this short N-terminal truncated fragment with an expanded repeat can aggregate in vitro (17).”
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“To determine if AT3 binds ubiquitylated proteins, cell lysates were incubated with MBP-AT3 and associated proteins pulled down with amylose beads.”
BackgroundInfluentialGlutamine repeats and neurodegenerative diseases: molecular aspects
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Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells
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“11, No. 23 2905–2917 sequences form aggregates (4,5, 14 ,15).”
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“One common pathologic feature of poly(Q) diseases is the formation of multimolecular aggregates that contain the disease protein (42,43).”
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“Strikingly, our mutations map of a polyglutamine (polyGln) tract (e.g., Paulson et al., exclusively within a short glutamine/asparagine-rich 1997; Scherzinger et al., 1997).”
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“…of extended polyQ polypeptides caused toxicity and neurodegeneration, and IBs in neurons were detectable, whereas polypeptides with polyQ of normal length were not toxic and did not form IBs (Davies et al., 1997; Scherzinger et al., 1997; Kazemi-Esfarjani and Benzer, 2000; Satyal et al., 2000).”
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In Situ Architecture and Cellular Interactions of PolyQ Inclusions
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“While polyQ-expanded Htt exon 1 forms fibrils in vitro (Scherzinger et al., 1997), it has remained controversial whether Htt in cellular inclusions is present in granular or fibrillar form (Finkbeiner, 2011; Qin et al., 2004; Waelter et al., 2001).”
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BackgroundInfluentialA Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation
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“In contrast, in vitro structural studies of HTTex1 aggregation have identified small rounded oligomers, amorphous aggregates, and fibrils with various dimensions, suggesting amore complexmechanism (Crick et al., 2013; Legleiter et al., 2010; Poirier et al., 2002; Scherzinger et al., 1997; Wetzel, 2012).”
A toxic monomeric conformer of the polyglutamine protein
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Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
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Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity
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“19 ± 21 Because of this, the only information we have on the biophysical behavior of longer poly(Gln) peptides comes from studies involving transiently soluble proteolytic fragments of recombinant poly(Gln)-containing proteins.(12,22) Recently, we devised a solvent treatment that renders poly(Gln) peptides up to repea…”
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“, which leads to its aggregation in nuclear and cytoplasmic inclusion bodie”
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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1997-08
- Volume
- 90
- Issue
- 3
- Pages
- 549-558
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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