Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis

Yaohui Chai, Jianqiang Shao, Victor M. Miller, Aislinn Williams, Henry L. Paulson

Research output: Contribution to journalArticle

159 Citations (Scopus)

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 proteintagged 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.

Original languageEnglish (US)
Pages (from-to)9310-9315
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number14
DOIs
StatePublished - Jul 9 2002
Externally publishedYes

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Proteins
Neurodegenerative Diseases
Fluorescence Recovery After Photobleaching
Photobleaching
Intranuclear Inclusion Bodies
Cyclic AMP Response Element-Binding Protein
Mutant Proteins
Green Fluorescent Proteins
polyglutamine
Fluorescence
Ataxin-3
Ataxin-1
Protein Aggregates

All Science Journal Classification (ASJC) codes

  • General

Cite this

Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. / Chai, Yaohui; Shao, Jianqiang; Miller, Victor M.; Williams, Aislinn; Paulson, Henry L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 14, 09.07.2002, p. 9310-9315.

Research output: Contribution to journalArticle

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