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FoxO3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of PUMA in a model of Parkinson's disease.

Parkinson's disease (PD) results from the selective loss of dopaminergic neurons of substantia nigra pars compacta region of the midbrain. It has been reported that the transcription factor forkhead Box O3a (FoxO3a) is activated and induces pro-apoptotic protein such as BIM (Bcl-2 interacting mediator of cell death) and PUMA (p53 upregulated modulator of apoptosis) in variety of neuron death paradigms. Activity of FoxO3a is governed by its post-translational modifications which control its sub-cellular localization. Aim of this study was to determine whether FoxO3a is activated and upregulates its pro-apoptotic genes to induce neuron death in PD. We exposed neuronal PC12 cells or primary cultures of dopaminergic neurons to 6-hydroxy dopamine (6-OHDA) and infused 6-OHDA in rat brain to develop PD models. We found that FoxO3a undergoes multiple post-translational modifications which render its nuclear localization in dopaminergic neuronal cells in response to 6-OHDA. The nuclear redistribution of FoxO3a is significantly increased in dopaminergic neurons of 6-OHDA infused rat brains as well. Moreover, FoxO3a is required for dopaminergic neurodegeneration in response to 6-OHDA as RNAi mediated silencing of FoxO3a protects these cells from 6-OHDA toxicity. In a search of the downstream targets we identified PUMA as a direct target of FoxO3a. By knocking down FoxO3a we could successfully block the upregulation of the pro-apoptotic protein PUMA in this model. Recently, it has been reported that chromatin remodeler SWI/SNF binds to FOXO and activates transcription. We found that Brg associated factor 57 (BAF57), a subclass of SWI/SNF is upregulated and play a necessary role in neuron death induced by 6-OHDA. Moreover, it is required for induction of PUMA by FoxO3a in this cellular model of PD. Taken together, our study suggest that FoxO3a is activated, translocates to nucleus, induces its pro-apoptotic target PUMA in presence of chromatin remodeler BAF57 to execute neuron death in cellular models of PD.