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(American Journal of Pathology. 2007;170:1725-1738.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061232

Calpain-Cleavage of -Synuclein

Connecting Proteolytic Processing to Disease-Linked Aggregation

Brian M. Dufty^*, Lisa R. Warner^*, Sheng T. Hou, Susan X. Jiang, Teresa Gomez-Isla, Kristen M. Leenhouts^*, Julia T. Oxford^*, Mel B. Feany, Eliezer Masliah^¶ and Troy T. Rohn^*

From the Department of Biology,^* Boise State University, Boise, Idaho; the Experimental NeuroTherapeutics Laboratory, National Research Council Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario, Canada; the Unidad de Memoria, Servicio de Neurologia, Hospital Santa Creu i Sant Pau, Barcelona, Spain; the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Neurosciences and Neuropathology,^¶ University of California, San Diego, La Jolla, California

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

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