Publication Date:
2006-06-24
Description:
Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1983366/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1983366/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cooper, Antony A -- Gitler, Aaron D -- Cashikar, Anil -- Haynes, Cole M -- Hill, Kathryn J -- Bhullar, Bhupinder -- Liu, Kangning -- Xu, Kexiang -- Strathearn, Katherine E -- Liu, Fang -- Cao, Songsong -- Caldwell, Kim A -- Caldwell, Guy A -- Marsischky, Gerald -- Kolodner, Richard D -- Labaer, Joshua -- Rochet, Jean-Christophe -- Bonini, Nancy M -- Lindquist, Susan -- P50 NS038372/NS/NINDS NIH HHS/ -- R01-HG002923/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2006 Jul 21;313(5785):324-8. Epub 2006 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16794039" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Animals, Genetically Modified
;
Caenorhabditis elegans
;
Cell Survival
;
Cells, Cultured
;
Disease Models, Animal
;
Dopamine/physiology
;
Drosophila
;
Endoplasmic Reticulum/*metabolism
;
Gene Expression
;
Gene Library
;
Golgi Apparatus/*metabolism
;
Humans
;
Mice
;
Nerve Degeneration
;
Neurons/cytology/*physiology
;
Parkinsonian Disorders/metabolism/pathology/*physiopathology
;
Proteasome Endopeptidase Complex/metabolism
;
Protein Folding
;
*Protein Transport
;
Proteins/chemistry/metabolism
;
Rats
;
Recombinant Fusion Proteins/metabolism
;
Saccharomyces cerevisiae/genetics/metabolism
;
Saccharomyces cerevisiae Proteins/genetics/metabolism
;
alpha-Synuclein/chemistry/genetics/*metabolism
;
rab GTP-Binding Proteins/genetics/metabolism
;
rab1 GTP-Binding Proteins/genetics/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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