Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis Revealed by Proteomic and Transcriptomic Analyses of the Striata in Two Mouse Models of Parkinson’s Disease

Abstract

The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson's disease (PD) are not completely understood. Here, we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 86 proteins with significant abundance changes following neurotoxin treatment. Similarly, microarray analyses revealed 181 genes with significant changes in mRNA, following neurotoxin treatment. The combined protein and gene list provides a clearer picture of the potential mechanisms underlying neurodegeneration observed in PD. Functional analysis of this combined list revealed a number of significant categories, including mitochondrial dysfunction, oxidative stress response, and apoptosis. These results constitute one of the largest descriptive data sets integrating protein and transcript changes for these neurotoxin models with many similar end point phenotypes but distinct mechanisms.

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

“…Moreover, the experimental approach allowed for identifying the pathways activated specifically by these toxins. For instance, a more pronounced decrease in protein levels was observed in the MPTP mice than in the METH model [109]. The majority of the proteins identified in this study functionally associate with apoptosis, which is likely to be due to mitochondrial dysfunction and oxidative damage.…”

“…In the study reported by Chin and colleagues, the downregulation of several anti-apoptotic and upregulation of pro-apoptotic genes and proteins were detected in both models [109]. For instance, the classic glycolytic protein glyceraldehyde-3-phosphate dehydrogenase, previously identified as a mediator of one or more apoptotic cascades and as a role-player in promoting LB formation [112], was found upregulated in both PD models.…”

“…Although the mitochondrial toxins MPTP and methamphetamine (METH) both induce parkinsonism in mice, MPTP results in the demise of neurons projecting to the striatum, whereas METH inhibits cell function and DA production without resulting in dopaminergic neuron death [109]. This difference in effect is believed to stem from a different mechanism of action between the two neurotoxins.…”

“…This difference in effect is believed to stem from a different mechanism of action between the two neurotoxins. The combination of proteomics (high-density liquid chromatography [LC] coupled to MS) with microarray ana lysis of the pooled left and right striata from mice previously exposed to MPTP compared with METH exposure culminated in a large descriptive data set on proteomic changes induced by these mitochondrial poisons [109]. Several of the proteins identified (n = 912) imply mitochondrial dysfunction and a cellular response to excessive oxidative stress, misregulated protein degradation, increased apoptosis and eventual cell death.…”

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

“…Such a complex pattern of cell impairment makes proteomics one of the most useful tools to integrate these modifications into a whole systematic picture. The reports that recently appeared on the proteomic analysis of amyloid diseases such as Alzheimer's disease, Parkinson's disease and others have provided valuable data on some cell modifications allowing to explain, at least in part, cell impairment in these diseases [12][13][14][15][16]. Proteomic studies provided useful information on the changes in pattern of protein expression in cells exposed to toxic aggregates of specific peptides/proteins found aggregated in the corresponding diseases.…”