Research

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

Liyan Qiao¹ , Shusei Hamamichi² , Kim A Caldwell^2,3,4,5 , Guy A Caldwell^2,3,4,5 , Talene A Yacoubian^3,4,5 , Scott Wilson³ , Zuo-Lei Xie¹ , Lisa D Speake¹ , Rachael Parks¹ , Donna Crabtree¹ , Qiuli Liang¹ , Stephen Crimmins¹ , Lonnie Schneider¹ , Yasuo Uchiyama⁶ , Takeshi Iwatsubo⁷ , Yi Zhou³ , Lisheng Peng⁸ , YouMing Lu⁸ , David G Standaert^3,4 , Ken C Walls¹ , John J Shacka^1,5,9 , Kevin A Roth^1,3,5 and Jianhua Zhang^1,3,5

¹  Department of Pathology, University of Alabama at Birmingham, Birmingham, USA

²  Department of Biological Sciences, The University of Alabama, Tuscaloosa, USA

³  Department of Neurobiology, University of Alabama at Birmingham, Birmingham, USA

⁴  Department of Neurology, University of Alabama at Birmingham, Birmingham, USA

⁵  Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, USA

⁶  Department of Cell Biology and Neurosciences, Osaka University, Osaka, Japan

⁷  Department of Neuropathology, Graduate School of Medicine, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

⁸  Biomolecular Science Center, Burnett College of Biomedical Sciences, Orlando, USA

⁹  Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, AL35294, USA

author email corresponding author email

Molecular Brain 2008, 1:17doi:10.1186/1756-6606-1-17

Published:	21 November 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.