Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease

Proteome Science

Research

Jie Shen¹  Tohru Kitada¹  Claus Zabel²  Joachim Klose²  Lei Mao²  Grit Nebrich²  Andrea Koppelstaetter²  Madeleine Diedrich² 

[1] Center for Neurologic Diseases, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School, 02115, Boston, MA, USA;Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, D-13353, Berlin, Germany;

关键词: Parkinson's disease;    mitophagy;    proteomics;    PINK1;    2DE;   

DOI  :  10.1186/1477-5956-9-59

 received in 2011-05-25, accepted in 2011-09-23,  发布年份 2011

来源: Springer

【 摘 要 】

Parkinson's disease (PD) is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO), in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS) pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia nigra. Taken together, the delicate balance between oxidative protection and mitophagy capacity in different brain regions could contribute to brain region-specific pathological patterns in PD.

【 授权许可】

Unknown   
© Diedrich et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.