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Series GSE60414 Query DataSets for GSE60414
Status Public on Nov 04, 2014
Title Potentiation of neurotoxicity in double mutant mice with Pink1 ablation and A53T-SNCA overexpression
Organism Mus musculus
Experiment type Expression profiling by array
Summary As the second most frequent neurodegenerative disorder of old age, Parkinson’s 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.
 
Overall design 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)
 
Contributor(s) Suzana G, Nadine B, Michael W, Georg A
Citation(s) 25296918
Submission date Aug 13, 2014
Last update date Aug 06, 2018
Contact name Michael H. Walter
E-mail(s) [email protected]
Organization name University of Tuebingen
Department Department of Medical Genetics
Lab The Microarray Facility Tübingen
Street address Calwer Str. 7
City Tuebingen
ZIP/Postal code 72076
Country Germany
 
Platforms (1)
GPL11180 [HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate
Samples (36)
GSM1479308 cerebellum_Pink1 -/- || A53T-SNCA_6 weeks_replicate 1
GSM1479309 cerebellum_Pink1 -/- || A53T-SNCA_6 weeks_replicate 2
GSM1479310 cerebellum_Pink1 -/- || A53T-SNCA_6 weeks_replicate 3
Relations
BioProject PRJNA258208

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE60414_RAW.tar 76.5 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table
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