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 Bcl‐2‐interacting mediator of cell death (BIM) and p53 up‐regulated modulator of apoptosis (PUMA) in variety of neuron death paradigms. Activity of FoxO3a is governed by its post‐translational modifications which control its subcellular localization. Aim of this study was to determine whether FoxO3a is activated and up‐regulates 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 up‐regulation of the pro‐apoptotic protein PUMA in this model. Recently, it has been reported that chromatin remodeler SWItch/sucrose non‐fermentable binds to FOXO and activates transcription. We found that Brg‐associated factor 57 (BAF57), a subclass of SWItch/sucrose non‐fermentable is up‐regulated 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 the presence of chromatin remodeler BAF57 to execute neuron death in cellular models of PD. image
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases that are presently incurable. There have been reports of aberrant activation of cell cycle pathways in neurodegenerative diseases. Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have synthesized a small library of molecules targeting Cdc25A and tested their neuroprotective potential in cellular models of neurodegeneration. The Buchwald reaction and amide coupling were crucial steps in synthesizing the Cdc25A-targeting molecules. Several of these small-molecule inhibitors significantly prevented neuronal cell death induced by nerve growth factor (NGF) deprivation as well as 6-hydroxydopamine (6-OHDA) treatment. Lack of NGF signaling leads to neuron death during development and has been associated with AD pathogenesis. The NGF receptor TrkA has been reported to be downregulated at the early stages of AD, and its reduction is linked to cognitive failure. 6-OHDA, a PD mimic, is a highly oxidizable dopamine analogue that can be taken up by the dopamine transporters in catecholaminergic neurons and can induce cell death by reactive oxygen species (ROS) generation. Some of our newly synthesized molecules inhibit Cdc25A phosphatase activity, block loss of mitochondrial activity, and inhibit caspase-3 activation caused by NGF deprivation and 6-OHDA. Hence, it may be proposed that Cdc25A inhibition could be a therapeutic possibility for neurodegenerative diseases and these Cdc25A inhibitors could be effective treatments for AD and PD.
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