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

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.

• 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
• Journal: Molecular brain (Mol Brain) Vol. 1 Pg. 17 (Nov 21 2008) ISSN: 1756-6606 [Electronic] England
• PMID: 19021916 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Neuroprotective Agents
• RNA, Messenger
• alpha-Synuclein
• Caspase 3
• Cathepsin D
• Ctsd protein, mouse
• Proteasome Endopeptidase Complex

Topics

• Animals
• Caenorhabditis elegans (drug effects)
• Caspase 3 (metabolism)
• Cathepsin D (deficiency, metabolism)
• Cell Line, Tumor
• Humans
• Lysosomes (drug effects, enzymology)
• Mice
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (metabolism)
• Phagosomes (drug effects, metabolism)
• Point Mutation (genetics)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Structure, Quaternary
• RNA, Messenger (genetics, metabolism)
• Up-Regulation (drug effects, genetics)
• alpha-Synuclein (genetics, metabolism, toxicity)