Proteomic profiling in MPTP monkey model for early Parkinson disease biomarker discovery

Abstract

Identification of reliable and robust biomarkers is crucial to enable early diagnosis of Parkinson disease (PD) and monitoring disease progression. While imperfect, the slow, chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced non-human primate animal model system of parkinsonism is an abundant source of pre-motor or early stage PD biomarker discovery. Here, we present a study of a MPTP rhesus monkey model of PD that utilizes complementary quantitative iTRAQ-based proteomic, glycoproteomics and phosphoproteomics approaches. We compared the glycoprotein, non-glycoprotein, and phosphoprotein profiles in the putamen of asymptomatic and symptomatic MPTP-treated monkeys as well as saline injected controls. We identified 86 glycoproteins, 163 non-glycoproteins, and 71 phosphoproteins differentially expressed in the MPTP-treated groups. Functional analysis of the data sets inferred the biological processes and pathways that link to neurodegeneration in PD and related disorders. Several potential biomarkers identified in this study have already been translated for their usefulness in PD diagnosis in human subjects and further validation investigations are currently under way. In addition to providing potential early PD biomarkers, this comprehensive quantitative proteomic study may also shed insights regarding the mechanisms underlying early PD development. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…MPP + can increase the synthesis of ROS by inducing the mitochondrial damage including decreased mitochondrial membrane potential, impaired respiratory chain complexes and release of cytochrome C [35][36][37]. The symptoms induced by MPTP are very similar to that of PD [29], suggesting that a long-term accumulation of certain endogenous neurotoxins, which have similar structure or function with MPTP, will lead to PD. Therefore, dopamine-derived alkaloids have been proposed as potential endogenous neurotoxins.…”

“…1-methyl-4-phenyl-2,3-dihydropyridium(MPTP) is a well-known exogenous neurotoxin, which has been widely used in animal models of PD [29][30][31][32]. MPTP was first discovered in the drugs, which made many addicts show signs of parkinsonism-like symptoms after they smoked them [33].…”

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

“…In this study, we conducted the proteome analysis of the ventral midbrain from two sophisticated mouse models of PD: -synuclein PFFs injection mouse model that represents sporadic PD (8) Mass spectrometry-based proteomics technologies have been widely used for the identification of proteins that are differentially expressed in disease animal models on a global scale (12)(13)(14)(15). To identify differentially expressed proteins, accurate quantifications of proteins are essential.…”

“…The proteomic findings from animal models of PD, such as MPTP-treated mouse model, 6-OHDA-injected rat model, and A30P*A53T α-synuclein transgenic mouse models, provided many valuable insights into several pathways that may be related to disease pathogenesis (12)(13)(14)(15).…”

Neuroproteomics — LC-MS Quantitative Approaches

“…In neuroproteomics, these approaches have been extensively used to characterize the differential proteomes of neuronal disorders, drug responses or brain regions. Many studies have been performed using these techniques in areas such as neurodegenerative disorders, as the study of the putamen proteome of an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease [101] or in the serum of Parkinson's disease patients [102], or even in the analysis of synaptossomes from cortical brain tissues from Alzheimer's disease patients [103]; in neuropharmacoproteomics, as in the examples of a study of protein quantitative alterations induced by antidepressants in the hippocampus of mice [104]; also in addiction as in the evaluation of the effects of administration of plasminogen activator after ischemic injury in mice [105] or the alterations upon chronic exposure to cocaine [106]; in neuropsychiatric and other CNS disorders, such as schizophrenia, with the study of protein expression in the thalamus and CSF of patients [107] and a study of neurofibromin knockdown PC12 cell line as a model of neurofibrimatosis [108]; or even in studies of neuronal function such as memory formation in hippocampus [109].…”