Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation

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TypeArticle
Journal titleAm.J.Pathol.
Volume170
Issue5
Pages17251738; # of pages: 14
SubjectAged; alpha-Synuclein; Animal; Animals; Antibodies; antibody; Area Under Curve; Blotting,Western; Brain; Calpain; Cell Line,Tumor; chemistry; DISEASE; Drosophila; Female; Fluorescent Antibody Technique; Human; Humans; Immunohistochemistry; Immunoprecipitation; Ischemia; Lewy Body Disease; Male; metabolism; Mice; Mice,Inbred C57BL; Mice,Transgenic; Middle Aged; MODEL; Neurons; Parkinson Disease; pathology; protease; Protein Structure,Secondary; STATE; structure; SYSTEM; SYSTEMS
AbstractParkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of alpha-synuclein (alpha-Syn), and although it is now recognized that alpha-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of alpha-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a beta-sheet structure. To determine whether calpain-cleavage of alpha-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to alpha-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved alpha-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved alpha-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved alpha-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of alpha-Syn in various alpha-synucleinopathies
Publication date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberDUFTY2007
NPARC number9370012
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Record identifier0a618bee-a178-433e-8b61-3b25c31f363d
Record created2009-07-10
Record modified2016-05-09
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