title: Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression.
abstract: The common age-related neurodegeneration of Parkinson's disease can result from dominant causes like increased dosage of vesicle-associated alpha-synuclein (SNCA) or recessive causes like deficiency of mitophagy factor PINK1. Interactions between these triggers and their convergence onto shared pathways are crucial, but currently conflicting evidence exists. Here, we crossed previously characterized mice with A53T-SNCA overexpression and with Pink1 deletion to generate double mutants (DMs). We studied their lifespan and behavior, histological and molecular anomalies at late and early ages. DM animals showed potentiated phenotypes in comparison with both single mutants (SMs), with reduced survival and strongly reduced spontaneous movements from the age of 3 months onwards. In contrast to SMs, a quarter of DM animals manifested progressive paralysis at ages >1 year and exhibited protein aggregates immunopositive for pSer129-SNCA, p62 and ubiquitin in spinal cord and basal brain. Brain proteome quantifications of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at the age of 18 months. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at the age of 6 weeks, which were absent from SMs. The observed downregulations for Dapk1, Dcaf17, Rab42 and the novel SNCA-marker Lect1 as well as the upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 and H2afx reflect changes in ubiquitination, mitochondrial/synaptic/microtubular/cell adhesion 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.
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Brehm
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Weil
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University Medical School, 60590 Frankfurt/Main, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University Medical School, 60590 Frankfurt/Main, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.affiliation: Institute of Neurophysiology, Neuroscience Center, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany and.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Kern
authors.affiliation: Institute for Medical Genetics, Eberhard-Karls-University of Tuebingen, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.affiliation: Institute of Neurophysiology, Neuroscience Center, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany, auburger@em.uni-frankfurt.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C497605:Snca protein, mouse