ReviewPhilosophical transactions of the Royal Society of London. Series B, Biological sciences1999
Polyglutamine pathogenesis.
Review in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 81 citations in OpenAlex.
- Structural-functional analyses of the huntingtin/HAP40 complex inJournal of biomolecular structure & dynamics · 2026Article
- Data mining revealed no other trinucleotide repeat expansion associated with the Huntington's disease biomarker (CAG).Clinical parkinsonism & related disorders · 2026Article
- Metal Ion Binding to Human Glutaminyl Cyclase: A Structural Perspective.International journal of molecular sciences · 2024Article
- Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions.Molecules (Basel, Switzerland) · 2017Review
- Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.Human molecular genetics · 2017Article
- Studying polyglutamine diseases in Drosophila.Experimental neurology · 2015Review
- RAN Translation in Huntington Disease.Neuron · 2015Article
- An Antibody to Detect Alanine-Expanded PABPN1: A New Tool to Study Oculopharyngeal Muscular Dystrophy.Journal of neuromuscular diseases · 2015Article
- Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast.PLoS genetics · 2012Article
- Human cytomegalovirus UL97 kinase prevents the deposition of mutant protein aggregates in cellular models of Huntington's disease and ataxia.Neurobiology of disease · 2011Article
- Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D(2) concept.Expert review of proteomics · 2010Review
- Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis.Human molecular genetics · 2010Article
- Cerebellar disorders--at the crossroad of molecular pathways and diagnosis.Cerebellum (London, England) · 2009Article
- Article
- Nucleocytoplasmic shuttling activity of ataxin-3.PloS one · 2009Article
- Mouse models of Huntington's disease and methodological considerations for therapeutic trials.Biochimica et biophysica acta · 2009Review
- Amyloidogenesis of natively unfolded proteins.Current Alzheimer research · 2008Review
- Ataxin-2 mediated cell death is dependent on domains downstream of the polyQ repeat.Experimental neurology · 2007Article
- Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation.Proceedings of the National Academy of Sciences of the United States of America · 2005Article
- Molecular origin of polyglutamine aggregation in neurodegenerative diseases.PLoS computational biology · 2005Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
An increasing number of neurodegenerative disorders have been found to be caused by expanding CAG triplet repeats that code for polyglutamine. Huntington's disease (HD) is the most common of these disorders and dentatorubral-pallidoluysian atrophy (DRPLA) is very similar to HD, but is caused by mutation in a different gene, making them good models to study. In this review, we will concentrate on the roles of protein aggregation, nuclear localization and proteolytic processing in disease pathogenesis. In cell model studies of HD, we have found that truncated N-terminal portions of huntingtin (the HD gene product) with expanded repeats form more aggregates than longer or full length huntingtin polypeptides. These shorter fragments are also more prone to aggregate in the nucleus and cause more cell toxicity. Further experiments with huntingtin constructs harbouring exogenous nuclear import and nuclear export signals have implicated the nucleus in direct cell toxicity. We have made mouse models of HD and DRPLA using an N-terminal truncation of huntingtin (N171) and full-length atrophin-1 (the DRPLA gene product), respectively. In both models, diffuse neuronal nuclear staining and nuclear inclusion bodies are observed in animals expressing the expanded glutamine repeat protein, further implicating the nucleus as a primary site of neuronal dysfunction. Neuritic pathology is also observed in the HD mice. In the DRPLA mouse model, we have found that truncated fragments of atrophin-1 containing the glutamine repeat accumulate in the nucleus, suggesting that proteolysis may be critical for disease progression. Taken together, these data lead towards a model whereby proteolytic processing, nuclear localization and protein aggregation all contribute to pathogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.