Premium
Reduction in endogenous parkin levels renders glial cells sensitive to both caspase‐dependent and caspase‐independent cell death
Author(s) -
MacCormac Luci P.,
Muqit Miratul M. K.,
Faulkes David J.,
Wood Nicholas W.,
Latchman David S.
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2004.03659.x
Subject(s) - parkin , programmed cell death , biology , microbiology and biotechnology , ubiquitin , caspase , ubiquitin ligase , transfection , apoptosis , staurosporine , cell culture , genetics , gene , signal transduction , parkinson's disease , medicine , disease , pathology , protein kinase c
Mutations in the parkin gene give rise to a familial form of Parkinson's disease, autosomal recessive juvenile Parkinsonism (AR‐JP). Although the exact mechanisms are unclear, it is thought that these ‘loss‐of‐function’ mutations contribute to the pathological process by interfering with parkin 's E3 ubiquitin ligase activity. In order to mimic the in vivo loss‐of‐function, we produced tet ‐inducible glial cell lines that, in the presence of doxycycline, were able either to under‐ or to over‐express the parkin protein. Using this cell‐culture system, we found that the induced alteration of parkin levels in glial cell lines caused different responses compared with their un‐induced counterparts under conditions of stress (staurosporine, hydrogen peroxide and dopamine). In particular, reduction in the levels of parkin within the transfected cells rendered them more susceptible to both apoptotic and necrotic cell death. Interestingly, blocking the cell death pathway with caspase inhibitors rescued the cells under‐expressing parkin from only some of the stress‐induced death. These findings implicate a pathogenic role of glial cells in the pathogenesis of AR‐JP caused by mutations in the parkin gene.