A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress.

Bou Dib, Peter; Gnägi, Bettina; Daly, Fiona; Sabado, Virginie; Tas, Damla; Glauser, Dominique A; Meister, Pierre; Nagoshi, Emi (2014). A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress. PLoS genetics, 10(10), e1004718. Public Library of Science 10.1371/journal.pgen.1004718

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bou Dib, Peter; Sabado, Virginie; Meister, Pierre and Nagoshi, Emi

Subjects:

500 Science > 570 Life sciences; biology

ISSN:

1553-7390

Publisher:

Public Library of Science

Language:

English

Submitter:

Pierre Meister

Date Deposited:

07 May 2015 10:59

Last Modified:

23 Feb 2016 08:30

Publisher DOI:

10.1371/journal.pgen.1004718

PubMed ID:

25340742

BORIS DOI:

10.7892/boris.68767

URI:

https://boris.unibe.ch/id/eprint/68767

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