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PMID: 16141322 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 37 ·2005-09-13 ·Pages 13135-40

Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, Kopito RR

Abstract

CNS neurons are endowed with the ability to recover from cytotoxic insults associated with the accumulation of proteinaceous aggregates in mouse models of polyglutamine disease, but the cellular mechanism underlying this phenomenon is unknown. Here, we show that autophagy is essential for the elimination of aggregated forms of mutant huntingtin and ataxin-1 from the cytoplasmic but not nuclear compartments. Human orthologs of yeast autophagy genes, molecular determinants of autophagic vacuole formation, are recruited to cytoplasmic but not nuclear inclusion bodies in vitro and in vivo. These data indicate that autophagy is a critical component of the cellular clearance of toxic protein aggregates and may help to explain why protein aggregates are more toxic when directed to the nucleus.

MeSH Terms
Ataxin-1 Ataxins Autophagy Autophagy-Related Protein 12 Autophagy-Related Protein 5 Cell Line Cell Nucleus/metabolism Cytoplasm/metabolism Humans Huntingtin Protein Huntington Disease Microtubule-Associated Proteins/metabolism Models, Biological Nerve Tissue Proteins/genetics,metabolism Nuclear Proteins/genetics,metabolism Peptides/metabolism Protein Transport Proteins/metabolism Small Ubiquitin-Related Modifier Proteins Spinocerebellar Ataxias Transfection
Chemicals
ATG12 protein, human ATG5 protein, human ATXN1 protein, human Ataxin-1 Ataxins Atxn1 protein, mouse Autophagy-Related Protein 12 Autophagy-Related Protein 5 HTT protein, human Huntingtin Protein Microtubule-Associated Proteins Nerve Tissue Proteins Nuclear Proteins Peptides Proteins Small Ubiquitin-Related Modifier Proteins polyglutamine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Iwata Atsushi
Department of Biological Sciences, BIO-X Program, Stanford University, Stanford, CA 94305-5430.
Christianson John C
Bucci Mirella
Ellerby Lisa M
Nukina Nobuyuki
Forno Lysia S
Kopito Ron R
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0505801102
Published
2005-09-13
Epub
2005-00-02
Pages
13135-40
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1201602
Subset
IM
Grants
NINDS NIH HHS · NS40251 · United States
NINDS NIH HHS · R56 NS042842 · United States
NINDS NIH HHS · NS042842 · United States
NINDS NIH HHS · R01 NS040251 · United States
NINDS NIH HHS · R01 NS042842 · United States
External Links
PubMed source DOI: 10.1073/pnas.0505801102 PMC Full Text View journal details
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