Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo  

作　　者：Xiaosen Ouyang Willayat Y.Wani Gloria A.Benavides Matthew J.Redmann Hai Vo Thomas van Groen Victor M.Darley-Usmar Jianhua Zhang 

机构地区：[1]Department of Pathology,University of Alabama at Birmingham,Birmingham,AL 35294,USA [2]Department of Cell,Developmental and Integrative Biology,University of Alabama at Birmingham,Birmingham,AL 35294,USA [3]Birmingham VA Medical Center,University of Alabama at Birmingham,Birmingham,AL 35294,USA

出　　处：《Acta Pharmaceutica Sinica B》2023年第10期4172-4184,共13页药学学报（英文版）

基　　金：partially supported by NIHR01-NS064090,R56AG060959,R01AG072895-01,I01 BX-003792,I01 BX004251(to Jianhua Zhang);UAB Neuroscience Core Facilities(NS47466,NS57098);UAB Blue Sky program;UAB Nathan Shock Center P30 AG050886。

摘　　要：The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control.Cathepsin D(CTSD),is one such lysosomal protease,which when deficient in humans lead to neurolipofuscinosis(NCL)and is important in removing toxic protein aggregates.Prior studies demonstrated that CTSD germ-line knockout-CtsdKO(CDKO)resulted in accumulation of protein aggregates,decreased proteasomal activities,and postnatal lethality on Day 26±1.Overexpression of wildtype CTSD,but not cathepsin B,L or mutant CTSD,decreased a-synuclein toxicity in worms and mammalian cells.In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA.After crossing with Nestin-cre,the STOP cassette is deleted in NESTIN+cells to allow CTSD overexpression-CTSDtg(CDtg).The CDtg mice exhibited normal behavior and similar sensitivity to subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)induced neurodegeneration.By breeding CDtg mice with CDKO mice,we found that over-expression of CTSD extended the lifespan of the CDKO mice,partially rescued proteasomal deficits and the accumulation of Aβ42 in the CDKO.This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo.

关 键 词：Cathepsin D transgenic mouse Mitochondrial bioenergetics Apoptosis Cathepsin D knockout mice DOPAMINE Autophagy LYSOSOME Life expectancy Behavior 

分 类 号：R749.16[医药卫生—神经病学与精神病学]