Potentiation of neurotoxicity in double mutant mice with Pink1 ablation and A53T-SNCA overexpression
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ABSTRACT: 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.
ORGANISM(S): Mus musculus
PROVIDER: GSE60414 | GEO | 2014/11/04
SECONDARY ACCESSION(S): PRJNA258208
REPOSITORIES: GEO
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