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

doi:10.1073/pnas.152101299

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

Journal article

Open access

Peer reviewed

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 and Henry L Paulson

Proceedings of the National Academy of Sciences - PNAS, Vol.99(14), pp.9310-9315

07/09/2002

DOI: 10.1073/pnas.152101299

PMCID: PMC123137

PMID: 12084819

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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.

Trinucleotide Repeats

Green Fluorescent Proteins

Heredodegenerative Disorders, Nervous System - genetics

Ataxin-3

CREB-Binding Protein

Repressor Proteins

Peptides - genetics

Nuclear Proteins - metabolism

Nerve Tissue Proteins - genetics

Recombinant Fusion Proteins - metabolism

Nerve Tissue Proteins - metabolism

Animals

Peptides - metabolism

Transfection

Heredodegenerative Disorders, Nervous System - etiology

Recombinant Fusion Proteins - genetics

Luminescent Proteins - genetics

Trans-Activators - metabolism

Heredodegenerative Disorders, Nervous System - metabolism

Models, Neurological

Mutation

COS Cells

Luminescent Proteins - metabolism

Details

Title: Subtitle: Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis
Creators: Yaohui Chai - Department of Neurology, 3160 Medical Labs, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Jianqiang Shao
Victor M Miller
Aislinn Williams
Henry L Paulson
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.99(14), pp.9310-9315
DOI: 10.1073/pnas.152101299
PMID: 12084819
PMCID: PMC123137
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: NS38712 / NINDS NIH HHS R01 NS038712 / NINDS NIH HHS
Language: English
Date published: 07/09/2002
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984066137902771

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