Mountain View
biomedical and healthCAre Data Discovery Index Ecosystem
help Advanced Search
Title: Potentiation of neurotoxicity in double mutant mice with Pink1 ablation and A53T-SNCA overexpression      
dateReleased:
11-04-2014
description:
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. 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)
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-60414
refinement:
raw
alternateIdentifiers:
60414
keywords:
functional genomics
dateModified:
11-08-2014
availability:
available
types:
gene expression
name:
Mus musculus
ID:
A-GEOD-11180
name:
[HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-60414/E-GEOD-60414.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-60414/E-GEOD-60414.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE60414
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

Feedback?

If you are having problems using our tools, or if you would just like to send us some feedback, please post your questions on GitHub.