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Detection of SNCA duplication aritifical mosaics

ABSTRACT: To determine sensitivity of a custom 8x60k aCGH design for mosaicism of SNCA gains, a peripheral blood lymphocyte (PBL) DNA sample with a known heterozygous duplication (CN 3, or 50% increase in SNCA) was diluted with a control (wild type, wt) sample (CN 2, screened by MLPA) to create "artifical mosaics" (CN 2.4, 2.3, 2,25, 2.2, 2.15, 2.1). Dilutions, as well as the undiluted heterozygous sample, and the control, were tested, hybridised with Agilent reference DNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71355 | GEO | 2016/02/01

SECONDARY ACCESSION(S): PRJNA291020

REPOSITORIES: GEO

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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)

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Detection of SNCA duplication aritifical mosaics

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