SCAMP5 links endoplasmic reticulum stress to the accumulation of expanded polyglutamine protein aggregates via endocytosis inhibition.
Accumulation of expanded polyglutamine proteins is considered to be a major pathogenic biomarker of Huntington disease. We isolated SCAMP5 as a novel regulator of cellular accumulation of expanded polyglutamine track protein using cell-based aggregation assays. Ectopic expression of SCAMP5 augments the formation of ubiquitin-positive and detergent-resistant aggregates of mutant huntingtin (mtHTT). Expression of SCAMP5 is markedly increased in the striatum of Huntington disease patients and is induced in cultured striatal neurons by endoplasmic reticulum (ER) stress or by mtHTT. The increase of SCAMP5 impairs endocytosis, which in turn enhances mtHTT aggregation. On the contrary, down-regulation of SCAMP5 alleviates ER stress-induced mtHTT aggregation and endocytosis inhibition. Moreover, stereotactic injection into the striatum and intraperitoneal injection of tunicamycin significantly increase mtHTT aggregation in the striatum of R6/2 mice and in the cortex of N171-82Q mice, respectively. Taken together, these results suggest that exposure to ER stress increases SCAMP5 in the striatum, which positively regulates mtHTT aggregation via the endocytosis pathway.
Noh
Jee-Yeon
JY
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Lee
Huikyong
H
Song
Sungmin
S
Kim
Nam Soon
NS
Im
Wooseok
W
Kim
Manho
M
Seo
Hyemyung
H
Chung
Chul-Woong
CW
Chang
Jae-Woong
JW
Ferrante
Robert J
RJ
Yoo
Young-Jun
YJ
Ryu
Hoon
H
Jung
Yong-Keun
YK
D000818:Animals; D001921:Brain / Q000196:embryology; D002352:Carrier Proteins / Q000378:metabolism*; D004705:Endocytosis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D015854:Up-Regulation
D002352:Carrier Proteins; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C540013:SCAMP5 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C097188:polyglutamine