RRC ID 4331
Author Kuwahara T, Koyama A, Koyama S, Yoshina S, Ren CH, Kato T, Mitani S, Iwatsubo T.
Title A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans.
Journal Hum Mol Genet
Abstract Mutations or multiplications in alpha-synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type alpha-synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating alpha-synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of alpha-synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human alpha-synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed alpha-synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in alpha-synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing alpha-synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. alpha-Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of alpha-synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated alpha-synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and alpha-synuclein-induced neurotoxicity in synucleinopathy.
Volume 17(19)
Pages 2997-3009
Published 2008-10-1
DOI 10.1093/hmg/ddn198
PII ddn198
PMID 18617532
MeSH Animals Animals, Genetically Modified / genetics Animals, Genetically Modified / metabolism Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Endocytosis* Humans Motor Activity Neurodegenerative Diseases / metabolism Neurodegenerative Diseases / physiopathology* Neurons / physiology* Neurotransmitter Agents / metabolism Phosphorylation RNA Interference* Synaptic Vesicles / metabolism* alpha-Synuclein / genetics* alpha-Synuclein / metabolism alpha-Synuclein / toxicity
IF 5.101
Times Cited 102
WOS Category GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
C.elegans tm2912