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Open Access 01-12-2008 | Research

Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

Authors: 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, Lisheng Peng, YouMing Lu, David G Standaert, Ken C Walls, John J Shacka, Kevin A Roth, Jianhua Zhang

Published in: Molecular Brain | Issue 1/2008

Abstract

α-synuclein (α-syn) is a 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. α-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 α-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous α-syn in neurons without overabundance of α-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 α-syn metabolism. Conversely, CD overexpression reduces α-syn aggregation and is neuroprotective against α-syn overexpression-induced cell death in vitro. In a C. elegans model, CD deficiency exacerbates α-syn accumulation while its overexpression is protective against α-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 α-syn degradation and identify CD as a novel target for LB disease therapeutics.

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Title: Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity
Authors: 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
Lisheng Peng
YouMing Lu
David G Standaert
Ken C Walls
John J Shacka
Kevin A Roth
Jianhua Zhang
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: Molecular Brain / Issue 1/2008
Electronic ISSN: 1756-6606
DOI: https://doi.org/10.1186/1756-6606-1-17

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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