title: DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human alpha-syn toxicity.
abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized alpha-synuclein (alpha-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of alpha-syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human alpha-syn (M83 mice) that develop extensive alpha-syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of alpha-syn inclusions, biochemical properties of alpha-syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate alpha-syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr alpha-syn in vivo. It is possible that alpha-syn and DJ-1 mutations may lead to PD via independent mechanisms.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
authors.forename: Chenere P
authors.initials: CP
authors.lastname: Ramsey
authors.forename: Elpida
authors.initials: E
authors.lastname: Tsika
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*
chemical_list: D015513:Oncogene Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1