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Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2002 Jul 09; Vol. 99 (14), pp. 9310-5. Date of Electronic Publication: 2002 Jun 25. - Publication Year :
- 2002
-
Abstract
- Protein misfolding and aggregation are central features of the polyglutamine neurodegenerative disorders, but the dynamic properties of expanded polyglutamine proteins are poorly understood. Here, we use fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) with green fluorescent protein fusion proteins to study polyglutamine protein kinetics in living cells. Our results reveal markedly divergent mobility states for an expanded polyglutamine protein, ataxin-3, and establish that nuclear inclusions formed by this protein are aggregates. Additional studies of green fluorescent protein-tagged cAMP response element binding protein coexpressed with either of two mutant polyglutamine proteins, ataxin-3 and huntingtin, support a model of disease in which coaggregation of transcriptional components contributes to pathogenesis. Finally, studies of a third polyglutamine disease protein, ataxin-1, reveal unexpected heterogeneity in the dynamics of inclusions formed by different disease proteins, a finding which may help explain disease-specific elements of pathogenesis in these neurodegenerative disorders.
- Subjects :
- Animals
Ataxin-3
COS Cells
CREB-Binding Protein
Green Fluorescent Proteins
Heredodegenerative Disorders, Nervous System etiology
Luminescent Proteins genetics
Luminescent Proteins metabolism
Models, Neurological
Mutation
Nerve Tissue Proteins genetics
Nuclear Proteins metabolism
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Repressor Proteins
Trans-Activators metabolism
Transfection
Trinucleotide Repeats
Heredodegenerative Disorders, Nervous System genetics
Heredodegenerative Disorders, Nervous System metabolism
Nerve Tissue Proteins metabolism
Peptides genetics
Peptides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 99
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 12084819
- Full Text :
- https://doi.org/10.1073/pnas.152101299