Parallel roles of transcription factors dFOXO and FER2 in the development and maintenance of dopaminergic neurons
| Autor: | Rafael Koch, Emi Nagoshi, Luca Stickley, Bettina Gnägi, Damla Tas, Virginie Sabado, Federico Miozzo, Nicolas Loncle |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Physiology Biochemistry Fats Animal Cells Medicine and Health Sciences Basic Helix-Loop-Helix Transcription Factors Drosophila Proteins Genetics (clinical) Energy-Producing Organelles Neurons Gene knockdown Movement Disorders Cell Death Drosophila Melanogaster Dopaminergic Eukaryota Neurodegenerative Diseases Parkinson Disease Forkhead Transcription Factors Animal Models Lipids Climbing Neuroprotection Cell biology Mitochondria Insects medicine.anatomical_structure Neurology Experimental Organism Systems Cell Processes Drosophila Cellular Types Cellular Structures and Organelles Research Article Programmed cell death lcsh:QH426-470 Arthropoda Cell Survival Autophagic Cell Death Biology Bioenergetics Research and Analysis Methods 03 medical and health sciences Model Organisms Genetics medicine Autophagy Animals Molecular Biology Transcription factor Ecology Evolution Behavior and Systematics Loss function Biological Locomotion Dopaminergic Neurons Organisms Biology and Life Sciences Cell Biology Invertebrates lcsh:Genetics Oxidative Stress 030104 developmental biology Cellular Neuroscience Mutation Neuron Neuroscience |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 14, Iss 3, p e1007271 (2018) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Forkhead box (FOXO) proteins are evolutionarily conserved, stress-responsive transcription factors (TFs) that can promote or counteract cell death. Mutations in FOXO genes are implicated in numerous pathologies, including age-dependent neurodegenerative disorders, such as Parkinson’s disease (PD). However, the complex regulation and downstream mechanisms of FOXOs present a challenge in understanding their roles in the pathogenesis of PD. Here, we investigate the involvement of FOXO in the death of dopaminergic (DA) neurons, the key pathological feature of PD, in Drosophila. We show that dFOXO null mutants exhibit a selective loss of DA neurons in the subgroup crucial for locomotion, the protocerebral anterior medial (PAM) cluster, during development as well as in adulthood. PAM neuron-targeted adult-restricted knockdown demonstrates that dFOXO in adult PAM neurons tissue-autonomously promotes neuronal survival during aging. We further show that dFOXO and the bHLH-TF 48-related-2 (FER2) act in parallel to protect PAM neurons from different forms of cellular stress. Remarkably, however, dFOXO and FER2 share common downstream processes leading to the regulation of autophagy and mitochondrial morphology. Thus, overexpression of one can rescue the loss of function of the other. These results indicate a role of dFOXO in neuroprotection and highlight the notion that multiple genetic and environmental factors interact to increase the risk of DA neuron degeneration and the development of PD. Author summary PD, mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN), is the most prevalent neurodegenerative movement disorder affecting more than 6 million people worldwide. Despite the discovery of several genes linked to familial PD, our understanding of its pathogenesis remains limited, as approximately 90% of the PD cases are sporadic with no apparent genetic linkage. Genome-wide expression studies have implicated the stress-responsive TF FOXO in PD. However, the exact role of FOXO in the survival of DA neurons and PD pathogenesis is still poorly understood. Here, we use fruit flies to address the role of FOXO in the maintenance of DA neurons. dFOXO (Drosophila FOXO) null mutants show a progressive loss of DA neurons in the subgroup essential for locomotion, a phenotype identical to that of Fer2 mutants. Remarkably, dFOXO and FER2 act in parallel pathways to protect PAM neurons from different cellular stressors, but both pathways contribute to the regulation of autophagy and mitochondrial biology. These results demonstrate that dFOXO is required for the maintenance of DA neurons important for locomotion and shed new light on the molecular mechanisms underpinning the complex gene-environment interactions affecting DA neuron survival and PD pathogenesis. |
| Databáze: | OpenAIRE |
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