Region-specific protein abundance changes in the brain of MPTP-induced Parkinson's disease mouse model.
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 potential nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 nonredundant 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 substantial MPTP-induced abundance changes across different brain regions. A total of 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 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. Ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-beta pathway, exhibited altered abundance 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.
Zhang
Xu
X
Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, P.O. Box 999, Richland, Washington 99352, USA.
Zhou
Jian-Ying
JY
Chin
Mark H
MH
Schepmoes
Athena A
AA
Petyuk
Vladislav A
VA
Weitz
Karl K
KK
Petritis
Brianne O
BO
Monroe
Matthew E
ME
Camp
David G
DG
Wood
Stephen A
SA
Melega
William P
WP
Bigelow
Diana J
DJ
Smith
Desmond J
DJ
Qian
Wei-Jun
WJ
Smith
Richard D
RD
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D004298:Dopamine