title: Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation.
abstract: Parkinson'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.
authors: Department of Biology, Boise State University, Boise, ID 83725, USA.
authors: Brian M
authors: BM
authors: Dufty
authors: Lisa R
authors: LR
authors: Warner
authors: Sheng T
authors: ST
authors: Hou
authors: Susan X
authors: SX
authors: Jiang
authors: Teresa
authors: T
authors: Gomez-Isla
authors: Kristen M
authors: KM
authors: Leenhouts
authors: Julia T
authors: JT
authors: Oxford
authors: Mel B
authors: MB
authors: Feany
authors: Eliezer
authors: E
authors: Masliah
authors: Troy T
authors: TT
authors: Rohn
mesh_terms: D000368:Aged; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004330:Drosophila; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D002154:Calpain