A Conserved Role for p48 Homologs in Protecting Dopaminergic Neurons from Oxidative Stress
نویسندگان
چکیده
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.
منابع مشابه
Roles of Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress
The loss of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease (PD). While the etiology of sporadic PD remains elusive, an inherited form of early-onset familial PD is linked to mutations of DJ-1. To understand the biological function of DJ-1 and its relevance to the pathogenesis of PD, we investigated the function of DJ-1 using Drosophila. Drosophi...
متن کاملOxidative stress and tardive dyskinesia: role of natural antioxidants
Schizophrenia is a devastating psychiatric disorder that affects 1% of population worldwide. Neuroleptics are the major class of drugs used in the treatment of schizophrenia. Neuroleptics are associated with wide variety of extrapyramidal side effects such as akathesia, dystonia, neuroleptic malignant syndrome, Parkinsonism and tardive dyskinesia. tardive dyskinesia is a complex hyperkinetic sy...
متن کاملOxidative stress and tardive dyskinesia: role of natural antioxidants
Schizophrenia is a devastating psychiatric disorder that affects 1% of population worldwide. Neuroleptics are the major class of drugs used in the treatment of schizophrenia. Neuroleptics are associated with wide variety of extrapyramidal side effects such as akathesia, dystonia, neuroleptic malignant syndrome, Parkinsonism and tardive dyskinesia. tardive dyskinesia is a complex hyperkinetic sy...
متن کامل6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33
Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA)...
متن کاملParkinson's disease proteins: Novel mitochondrial targets for cardioprotection
Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to...
متن کامل