Abstract
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.
Highlights
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN)
To determine whether dFOXO is involved in the control of brain DA neuron viability, we assessed the integrity of DA neurons by immunostaining with anti-tyrosine hydroxylase (TH) antibodies in dfoxo null mutants, dfoxoΔ94 [32]
To distinguish the loss of TH expression and neuronal loss, we drove the expression of nuclear-targeted RFP (RedStinger) with R58E02-GAL4, which is expressed in pupal and adult protocerebral anterior medial (PAM) neurons [33, 34], in dfoxoΔ94/+ and dfoxoΔ94 flies
Summary
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Mitochondrial dysfunction and elevated oxidative stress–two major cellular pathogenic characteristics in PD patients’ brains [13]–have been observed in many genetic fly models of PD [14,15,16,17,18]. Despite these advances in the study of familial PD pathogenesis, the mechanistic understanding of sporadic PD, which accounts for approximately 90% of PD cases, is lagging behind
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
