Calpain-Cleavage of α-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation

Authors

Brian M. Dufty, Boise State University
Lisa R. Warner, Boise State UniversityFollow
Kristen M. Leenhouts, Boise State University
Julia T. Oxford, Boise State UniversityFollow
Troy T. Rohn, Boise State UniversityFollow

Document Type

Article

Publication Date

5-1-2007

DOI

http://dx.doi.org/10.2353/ajpath.2007.061232

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 α-synuclein (α-Syn), and although it is now recognized that α-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 α-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a β-sheet structure. To determine whether calpain-cleavage of α-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to α-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved α-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 α-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved α-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 α-Syn in various α-synucleinopathies.

Comments

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Publication Information

Dufty, Brian M.; Warner, Lisa R.; Leenhouts, Kristen M.; Oxford, Julia T.; and Rohn, Troy T.. (2007). "Calpain-Cleavage of α-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation". The American Journal of Pathology, 170(5), 1725-38.