Upregulation of cathepsin D in the caudate nucleus of primates with experimental parkinsonism

Molecular Neurodegeneration

Howard S Fox¹  Claudia T Flynn³  Amrita Datta Chaudhuri²  Sowmya V Yelamanchili² 

[1] Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA

关键词: nonhuman primate;    apoptosis;    cathepsin;    neurodegeneration;    caudate;    striatum;    MPTP;    Parkinson's;   

Others  :  865743
DOI  :  10.1186/1750-1326-6-52

 received in 2010-10-14, accepted in 2011-07-21,  发布年份 2011

【 摘 要 】

Background

In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease.

Results

Using chronic 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis.

Conclusions

Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.

【 授权许可】

   
2011 Yelamanchili et al; licensee BioMed Central Ltd.

【 图 表 】

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