Dataset Information

SWATH-MS Analysis of Striatal Synaptic Mitochondria from Pink1 KO rats

ABSTRACT: This study investigates the proteomic alterations in striatal synaptic mitochondria isolated from 3-month-old wild-type and Pink1 KO rats using the SWATH-MS strategy. This dataset consists of 32 raw MS files, comprising 8 DIA (SWATH) and 24 DDA runs on a TripleTOF 5600 (SCIEX). Our findings revealed synaptic mitochondrial proteomic changes due to loss of Pink1.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Kelly Stauch

LAB HEAD: Howard S Fox

PROVIDER: PXD004558 | Pride | 2016-09-28

REPOSITORIES: Pride

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Publications

Loss of Pink1 modulates synaptic mitochondrial bioenergetics in the rat striatum prior to motor symptoms: concomitant complex I respiratory defects and increased complex II-mediated respiration.

Stauch Kelly L KL Villeneuve Lance M LM Purnell Phillip R PR Ottemann Brendan M BM Emanuel Katy K Fox Howard S HS

Proteomics. Clinical applications 20160921 12

<h4>Purpose</h4>Mutations in PTEN-induced putative kinase 1 (Pink1), a mitochondrial serine/threonine kinase, cause a recessive inherited form of Parkinson's disease (PD). Pink1 deletion in rats results in a progressive PD-like phenotype, characterized by significant motor deficits starting at 4 months of age. Despite the evidence of mitochondrial dysfunction, the pathogenic mechanism underlying disease due to Pink1-deficiency remains obscure.<h4>Experimental design</h4>Striatal synaptic mitocho ...[more]

PMID: 27568932

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Project description:As the second most frequent neurodegenerative disorder of old age, ParkinsonM-bM-^@M-^Ys disease (PD) can result from autosomal dominant causes like increased alpha-synuclein (SNCA) dosage, or from autosomal recessive causes like PINK1 loss-of-function. Interactions between these triggers and their potential convergence onto shared pathways are crucial to understand, but currently conflicting evidence exists. Here, we crossed previously characterized mice with A53T-SNCA overexpression and mice with PINK1 deletion to generate double mutants (DM). We studied their lifespan and behavior, together with histological and molecular anomalies at late and early ages, respectively. DM animals showed potentiated phenotypes in comparison to both single mutants (SM), with markedly reduced survival after age 450 days and strongly reduced spontaneous movements from age 3 months onwards. A considerable part of DM animals manifested progressive paralysis at ages >1 year and also exhibited protein aggregates with immunoreactivity for pSer129-SNCA, p62, and ubiquitin in spinal cord and basal brain, contrasting with absence of such features from SM. A brain proteome quantification of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at age 18 months. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at age 6 weeks, which were absent from SM. The observed downregulations for Dapk1, Dcaf17, Rab42 and upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 reflect changes in ubiquitination, mitochondrial / synaptic / microtubular dynamics, and DNA damage. Thus, our study confirmed that SNCA-triggered neurotoxicity is exacerbated by the absence of PINK1, and identified a novel molecular signature that is detectable early in the course of this double pathology. Factorial design comparing Pink1 knock-out/A53T-SNCA double transgenic mice with appropriate wild-type controls (129SvEv+FVB/N) in three different tissues (cerebellum, midbrain, striatum)

			Action	DRS
	DDA_Raw_File.zip	Other
	DIA_Raw_File.zip	Other
	Results_File.zip	Other
	Search_Identification_File.zip	Other