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
Mutant Huntingtin reduces HSP70 expression through the sequestration of NF‐Y transcription factor
Yamanaka, T., Miyazaki, H., Oyama, F., Kurosawa, M., Washizu, C., Doi, H., & Nukina, N. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.23 · Cited by 126
The role of amyloid oligomers in neurodegenerative pathologies
Wells, C., Brennan, S. E., Keon, M., & Ooi, L. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.03.113 · Cited by 131
Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3
Haacke, A., Broadley, S. A., Boteva, R. N., Tzvetkov, N., Hartl, F. U., & Breuer, P. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddi472 · Cited by 128
“Several dilutions (corresponding to 5–75 pmol of GST-fusion protein) were filtered through a cellulose acetate membrane (0.2 mm pores, Schleicher & Schuell) (32).”
BackgroundMethodInfluential
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease
Benn, C., Landles, C., He, L., Strand, A. D., Woodman, B., Sathasivam, K., Li, S.-H., Ghazi‐Noori, S., Hockly, E., Faruque, S. M. N. N., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi340 · Cited by 131
“Primary antibodies and dilutions were S830 (1:750), pAb (43); Mek1 (1:3000), pAb (Santa Cruz Biotech); Histone 2b (1:400), pAb (Chemicon); a-tubulin (1:500), mAb (Sigma); b-actin (1:5000), mAb (Abcam Ltd); CAG53b (1:5000), pAb ( 44 ); a-HDAC1 (1:10 000), pAb (gift from C. Seiser) and MOBP (1:1000), pAb (Santa Cruz Bio…”
Self-citation
Genetic Study of Interactions Between the Cytoskeletal Assembly Protein Sla1 and Prion-Forming Domain of the Release Factor Sup35 (eRF3) in Saccharomyces cerevisiae
Bailleul, P. A., Newnam, G. P., Steenbergen, J. N., & Chernoff, Y. O. (1999) · Genetics · doi:10.1093/genetics/153.1.81 · Cited by 125
Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motoneuronal processes
Piccioni, F., Pinton, P., Simeoni, S., Pozzi, P., Fascio, U., Vismara, G., Martini, L., Rizzuto, R., & Poletti, A. (2002) · The FASEB Journal · doi:10.1096/fj.01-1035fje · Cited by 123
“A common feature of all polyGln-related diseases is the intracellular formation of insoluble aggregates formed by the mutated proteins in the cell nucleus and/or cytoplasm (15-38).”
Background
Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation
Morton, A. J., Lagan, M., Skepper, J. N., & Dunnett, S. B. (2000) · Journal of Neurocytology · doi:10.1023/a:1010887421592 · Cited by 123
Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease
Shehadeh, J., Fernandes, H. B., Mullins, M. Z., Graham, R. K., Leavitt, B. R., Hayden, M. R., & Raymond, L. A. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.08.001 · Cited by 120
“Htt fragments with expanded polyQ form neuronal nuclear and cytoplasmic oligomers (Davies et al., 1997; DiFiglia et al., 1997; Scherzinger et al., 1997) that are toxic to neurons by a variety of mechanisms (Sapp et al., 1999; Cha, 2000; Goellner and Rechsteiner, 2003; Gunawardena et al., 2003;…”
Background
Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
Arnoux, I., Willam, M., Griesche, N., Krummeich, J., Watari, H., Offermann, N., Weber, S. S., Dey, P. N., Chen, C., Monteiro, O., et al. (2018) · eLife · doi:10.7554/elife.38744 · Cited by 117
“HEKT cell lines (ATCC, RRID:CVCL_1926) stably expressing FLAG-tagged HTT-exon 1 with either 51 or 83 CAG repeats under the control of a Tet-off promotor as well as the filter retardation assay were described previously (Scherzinger et al., 1997).”
MethodSelf-citation
Identification of Novel Potentially Toxic Oligomers Formed in Vitro from Mammalian-derived Expanded huntingtin Exon-1 Protein
Nucifora, L. G., Burke, K. A., Feng, X., Arbez, N., Zhu, S., Miller, J. M. L., Yang, G., Ratovitski, T., Delannoy, M. R., Muchowski, P. J., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.252577 · Cited by 121
RNA-binding Protein TLS Is a Major Nuclear Aggregate-interacting Protein in Huntingtin Exon 1 with Expanded Polyglutamine-expressing Cells
Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m705306200 · Cited by 119
Characterization of the Structure and the Amyloidogenic Properties of the Josephin Domain of the Polyglutamine-containing Protein Ataxin-3
Masino, L., Nicastro, G., Menon, R. P., Piaz, F. D., Calder, L. J., & Pastore, A. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.09.065 · Cited by 119
Ataxin-3 is transported into the nucleus and associates with the nuclear matrix
Tait, D. S. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.6.991 · Cited by 119
“As neuronal nuclear inclusions containing huntingtin aggregates have been detected in transgenic mice expressing a fragment (exon 1) of the HD gene (18,19) as well as in the brain of HD patients (11), in the future the nuclear distribution of huntingtin needs to be analysed in more detail in HD patients.”
Background
Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties
Riguet, N., Mahul-Mellier, A.-L., Maharjan, N., Burtscher, J., Croisier, M., Knott, G., Hastings, J., Patin, A., Reiterer, V., Farhan, H., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26684-z · Cited by 118
Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy
Abu-Baker, A. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg293 · Cited by 118
“Since insoluble mPABPN1–ala17 cannot be adequately quantified by western blotting (12), we used a filter trap assay (59,60) for quantitative analysis of insoluble form of the mutant PABPN1.”
Method
Huntingtin in health and disease
Young, A. B. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17742 · Cited by 118
Dementia with Lewy Bodies. A Distinct Non‐Alzheimer Dementia Syndrome?
Ince, P. G., Perry, E. K., & Morris, C. M. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00156.x · Cited by 116
The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease
Chai, Y., Wu, L., Griffin, J. D., & Paulson, H. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106575200 · Cited by 116
Development of a Human Light Chain Variable Domain (VL) Intracellular Antibody Specific for the Amino Terminus of Huntingtin via Yeast Surface Display
Colby, D. W., Garg, P., Holden, T., Chao, G., Webster, J. M., Messer, A. C., Ingram, V. M., & Wittrup, K. D. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.07.054 · Cited by 116
Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain
Dı́az-Hernández, M., Valera, A. G., Morán, M. A., Gómez‐Ramos, P., Alvarez‐Castelao, B., Castaño, J. G., Hernández, F., & Lucas, J. J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03968.x · Cited by 116
“In vitro aggregation studies revealed formation of protein aggregates when the polyQ expansion is in the pathogenic range, and that these aggregates have fibrillar morphology and can be stained with amyloid dyes (Scherzinger et al. 1997).”
Background
Atomistic Simulations of the Effects of Polyglutamine Chain Length and Solvent Quality on Conformational Equilibria and Spontaneous Homodimerization
Vitalis, A., Wang, X., & Pappu, R. V. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.09.026 · Cited by 116
The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges
Tundo, G. R., Sbardella, D., Santoro, A. M., Coletta, A., Oddone, F., Grasso, G., Milardi, D., Lacal, P. M., Marini, S., Purrello, R., et al. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107579 · Cited by 120
Mutant huntingtin represses CBP, but not p300, by binding and protein degradation
Cong, S., Pepers, B. A., Evert, B. O., Rubinsztein, D. C., Roos, R. A. C., van Ommen, G. B., & Dorsman, J. C. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.05.003 · Cited by 117
Assessing the contribution of heterogeneous distributions of oligomers to aggregation mechanisms of polyglutamine peptides
Vitalis, A., & Pappu, R. V. (2011) · Biophysical Chemistry · doi:10.1016/j.bpc.2011.04.006 · Cited by 106
“Products of proteolysis are rich in unprocessed polyglutamine regions [22, 23], which are prone to aggregation [6, 24-30] as well as recruitment and sequestration [6, 31, 32] of polyglutamine-rich regions from other proteins, specifically transcription factors [33-46].”
BackgroundMethod
Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin
Yang, H., Zhong, X., Ballar, P., Luo, S., Shen, Y., Rubinsztein, D. C., Monteiro, M. J., & Fang, S. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.10.031 · Cited by 116
Atrophin-1, the Dentato-Rubral and Pallido-Luysian Atrophy Gene Product, Interacts with Eto/Mtg8 in the Nuclear Matrix and Represses Transcription
Wood, J., Nucifora, F. C., Duan, K., Zhang, C., Wang, J., Kim, Y., Schilling, G., Sacchi, N., Liu, J. M., & Ross, C. A. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.150.5.939 · Cited by 114
“Polyglutamine-containing proteins have an inherent ability to aggregate when the length of the polyglutamine tract exceeds the aforementioned critical threshold (Scherzinger et al., 1997).”
Background
Ubiquitin–proteasome system involvement in Huntington’s disease
Ortega, Z., & Lucas, J. J. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00077 · Cited by 117
Sensitive biochemical aggregate detection reveals aggregation onset before symptom development in cellular and murine models of Huntington’s disease
Weiss, A., Klein, C., Woodman, B., Sathasivam, K., Bibel, M., Régulier, E., Bates, G. P., & Paganetti, P. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05032.x · Cited by 116
“More precise biochemical quantitative information can be obtained with the filter-trap assay for aggregates (Scherzinger et al. 1997).”
BackgroundSelf-citation
Yeast [PSI+] “Prions” that Are Crosstransmissible and Susceptible beyond a Species Barrier through a Quasi-Prion State
Nakayashiki, T., Ebihara, K., Bannai, H., & Nakamura, Y. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00259-3 · Cited by 113
Huntingtin and Mutant SOD1 Form Aggregate Structures with Distinct Molecular Properties in Human Cells
Matsumoto, G., Kim, S., & Morimoto, R. I. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509201200 · Cited by 112
Super-resolving Microscopy in Neuroscience
Werner, C. D., Sauer, M., & Geis, C. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01174 · Cited by 113
Hsp104: A Weapon to Combat Diverse Neurodegenerative Disorders
Shorter, J. (2007) · Neurosignals · doi:10.1159/000109760 · Cited by 113
Mammalian, Yeast, Bacterial, and Chemical Chaperones Reduce Aggregate Formation and Death in a Cell Model of Oculopharyngeal Muscular Dystrophy
Bao, Y. P., Cook, L. J., O’Donovan, D. G., Uyama, E., & Rubinsztein, D. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109633200 · Cited by 112

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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