Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity.
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.
Qiao
Liyan
L
Department of Pathology, University of Alabama at Birmingham, USA. lqiao@uab.edu
Hamamichi
Shusei
S
Caldwell
Kim A
KA
Caldwell
Guy A
GA
Yacoubian
Talene A
TA
Wilson
Scott
S
Xie
Zuo-Lei
ZL
Speake
Lisa D
LD
Parks
Rachael
R
Crabtree
Donna
D
Liang
Qiuli
Q
Crimmins
Stephen
S
Schneider
Lonnie
L
Uchiyama
Yasuo
Y
Iwatsubo
Takeshi
T
Zhou
Yi
Y
Peng
Lisheng
L
Lu
YouMing
Y
Standaert
David G
DG
Walls
Ken C
KC
Shacka
John J
JJ
Roth
Kevin A
KA
Zhang
Jianhua
J
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002402:Cathepsin D / Q000172:deficiency / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
D018696:Neuroprotective Agents; D012333:RNA, Messenger; D051844:alpha-Synuclein; D053148:Caspase 3; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D046988:Proteasome Endopeptidase Complex