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Title: Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 non-redundant proteins with at least two unique peptides per protein. The relative abundance changes in each analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with significant MPTP-induced changes across different brain regions. 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit significant abundance changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change acrossmore » all brain regions or with changes specific to the cortex and cerebellum regions were also detected. One of the interesting proteins is ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-β pathway, which exhibited altered abundances in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
974950
Report Number(s):
PNNL-SA-67444
24698; 3567b; 400412000; TRN: US201007%%904
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Proteome Research, 9(3):1496-1509; Journal Volume: 9; Journal Issue: 3
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ABUNDANCE; APOPTOSIS; BRAIN; CALCIUM; CEREBELLUM; DISEASES; DOPAMINE; ENZYMES; FUNCTIONALS; NERVE CELLS; PEPTIDES; PROTEINS; VALIDATION; Environmental Molecular Sciences Laboratory

Citation Formats

Zhang, Xu, Zhou, Jianying, Chin, Mark H, Schepmoes, Athena A, Petyuk, Vladislav A, Weitz, Karl K, Petritis, Brianne O, Monroe, Matthew E, Camp, David G, Wood, Stephen A, Melega, William P, Bigelow, Diana J, Smith, Desmond J, Qian, Weijun, and Smith, Richard D. Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model. United States: N. p., 2010. Web. doi:10.1021/pr901024z.
Zhang, Xu, Zhou, Jianying, Chin, Mark H, Schepmoes, Athena A, Petyuk, Vladislav A, Weitz, Karl K, Petritis, Brianne O, Monroe, Matthew E, Camp, David G, Wood, Stephen A, Melega, William P, Bigelow, Diana J, Smith, Desmond J, Qian, Weijun, & Smith, Richard D. Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model. United States. doi:10.1021/pr901024z.
Zhang, Xu, Zhou, Jianying, Chin, Mark H, Schepmoes, Athena A, Petyuk, Vladislav A, Weitz, Karl K, Petritis, Brianne O, Monroe, Matthew E, Camp, David G, Wood, Stephen A, Melega, William P, Bigelow, Diana J, Smith, Desmond J, Qian, Weijun, and Smith, Richard D. Mon . "Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model". United States. doi:10.1021/pr901024z.
@article{osti_974950,
title = {Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model},
author = {Zhang, Xu and Zhou, Jianying and Chin, Mark H and Schepmoes, Athena A and Petyuk, Vladislav A and Weitz, Karl K and Petritis, Brianne O and Monroe, Matthew E and Camp, David G and Wood, Stephen A and Melega, William P and Bigelow, Diana J and Smith, Desmond J and Qian, Weijun and Smith, Richard D},
abstractNote = {Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 non-redundant proteins with at least two unique peptides per protein. The relative abundance changes in each analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with significant MPTP-induced changes across different brain regions. 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit significant abundance changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change across all brain regions or with changes specific to the cortex and cerebellum regions were also detected. One of the interesting proteins is ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-β pathway, which exhibited altered abundances in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.},
doi = {10.1021/pr901024z},
journal = {Journal of Proteome Research, 9(3):1496-1509},
number = 3,
volume = 9,
place = {United States},
year = {Mon Feb 15 00:00:00 EST 2010},
month = {Mon Feb 15 00:00:00 EST 2010}
}