A Conserved Role for p48 Homologs in Protecting Dopaminergic Neurons from Oxidative Stress

Article Article scientifique Article A Conserved Role for p48 Homologs in Protecting Dopaminergic Neurons from Oxidative Stress eng 2014 author Bou Dib Peter author Gnägi Bettina author Daly Fiona Barbara 822833 author Sabado Virginie 813271 author Tas Damla 811731 author Glauser Dominique A. author Meister Peter author Nagoshi Emi 0000-0002-6365-4074 535940 e1004718 10.1371/journal.pgen.1004718 1553-7390 http://dx.plos.org/10.1371/journal.pgen.1004718 Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Both environmental and genetic factors are thought to contribute to the pathogenesis of PD. Although several genes linked to rare familial PD have been identified, endogenous risk factors for sporadic PD, which account for the majority of PD cases, remain largely unknown. Genome-wide association studies have identified many single nucleotide polymorphisms associated with sporadic PD in neurodevelopmental genes including the transcription factor p48/ptf1a. Here we investigate whether p48 plays a role in the survival of DA neurons in Drosophila melanogaster and Caenorhabditis elegans. We show that a Drosophila p48 homolog, 48-related-2 (Fer2), is expressed in and required for the development and survival of DA neurons in the protocerebral anterior medial (PAM) cluster. Loss of Fer2 expression in adulthood causes progressive PAM neuron degeneration in aging flies along with mitochondrial dysfunction and elevated reactive oxygen species (ROS) production, leading to the progressive locomotor deficits. The oxidative stress challenge upregulates Fer2 expression and exacerbates the PAM neuron degeneration in Fer2 loss-of-function mutants. hlh-13, the worm homolog of p48, is also expressed in DA neurons. Unlike the fly counterpart, hlh-13 loss-of-function does not impair development or survival of DA neurons under normal growth conditions. Yet, similar to Fer2, hlh-13 expression is upregulated upon an acute oxidative challenge and is required for the survival of DA neurons under oxidative stress in adult worms. Taken together, our results indicate that p48 homologs share a role in protecting DA neurons from oxidative stress and degeneration, and suggest that loss-of-function of p48 homologs in flies and worms provides novel tools to study gene-environmental interactions affecting DA neuron survival. Dewey 590 44 Département de génétique et évolution 162 false PLOS genetics 10 10 3364c830-ccaf-4f5f-8eab-6fd8d04d4ad9 Article (Published version) Public journal.pgen.1004718.PDF 2067800 application/pdf openAccess Faculté des sciences / Section de biologie / Département de génétique et évolution

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A Conserved Role for p48 Homologs in Protecting Dopaminergic Neurons from Oxidative Stress	PLOS genetics			2014	584	250

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Daly, Fiona Barbara