Premium
P3–446: Significant reduction in 6–hydroxy–dopamine nigral lesion size by administration of clioquinol
Author(s) -
Wilkins Simon,
Deleva Karoline,
Cortes Mikhalina,
San Mok Su,
Culvenor Janetta G.,
Vais Angela,
Finkelstein David I.,
Masters Colin L.,
Cappai Roberto,
Barnham Kevin J.,
Bush Ashley I.,
Cherny Robert A.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1717
Subject(s) - clioquinol , dopamine , dopaminergic , substantia nigra , neurotoxin , mptp , chemistry , lesion , parkinson's disease , pharmacology , toxicity , neurodegeneration , neuron , neuroscience , medicine , biochemistry , biology , pathology , disease
characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs is the presence of fibrillary aggregates of alpha-synuclein (alpha-Syn). Although it is now well recognized that alpha-Syn is the major building block of the filaments that form the pathological inclusions characteristic of LBs, the mechanism of how this occurs remains unknown. In the present study, we show that the ubiquitous protease, calpain I, can cleave alpha-Syn in vitro leading to its aggregation. To determine whether calpain can cleave alpha-Syn in PD and DLB, we designed a site-directed calpain cleavage antibody to alpha-Syn. Following in vitro characterization of this antibody termed alpha-Syn CCP (calpain cleavage product) Ab, we performed immunohistochemistry using postmortem brain sections from PD or DLB brains. Evidence for the calpain cleavage of alpha-Syn was found in both DLB and in PD brains. In DLB, 70% of identified LBs had the presence of calpain-cleaved alphaSyn. These results support a role for calpain in the proteolytic processing of alpha-Syn and suggest that this protease may link the processing of alpha-Syn to LB formation. Supported by NIH/NCRR grant # P20RR016454.