Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity
alpha-synuclein (alpha-syn) isa main component of Lewy bodies (LB) that occur in many neurodegenerative diseases, including Parkinson's disease (PD), dementia with LB (DLB) and multi-system atrophy. alpha-syn mutations or amplifications are responsible for a subset of autosomal dominant familial PD cases, and overexpression causes neurodegeneration and motor disturbances in animals.
To investigate mechanisms for alpha-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous alpha-syn in neurons without overabundance of alpha-syn mRNA. In addition to impaired macroautophagy, CD deficiency reduced proteasome activity, suggesting an essential role for lysosomal CD function in regulating multiple proteolytic pathways that are important for alpha-syn metabolism.
Conversely, CD overexpression reduces alpha-syn aggregation and is neuroprotective against alpha-syn overexpression-induced cell death in vitro. In a C.
elegans model, CD deficiency exacerbates alpha-syn accumulation while its overexpression is protective against alpha-syn-induced dopaminergic neurodegeneration. Mutated CD with diminished enzymatic activity or overexpression of cathepsins B (CB) or L (CL) is not protective in the worm model, indicating a unique requirement for enzymatically active CD.
Our data identify a conserved CD function in alpha-syn degradation and identify CD as a novel target for LB disease therapeutics.
Author: Liyan Qiao, Shusei Hamamichi, Kim A Caldwell, Guy A Caldwell, Talene A Yacoubian, Scott Wilson, Zuo-Lei Xie, Lisa D Speake, Rachael Parks, Donna Crabtree, Qiuli Liang, Stephen Crimmins, Lonnie Schneider, Yasuo Uchiyama, Takeshi Iwatsubo, Yi Zhou,
Published on: 2008-11-21
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