Forkhead Box O3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of p53 up‐regulated modulator of apoptosis (Puma) in a model of Parkinson’s disease

Abstract

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

Exosome-derived miR-128 is decreased in Parkinson’s patient plasma that maintains synaptic integrity and protects against both intrinsic and extrinsic pathways of neuronal apoptosis in models of Parkinson’s disease

“…Using standard in vitro models of PD, our uorescent imaging and ow cytometry-based experiments respectively showed that miR-128 over-expression could attenuate the production of mitochondrial superoxide radicals as well as prevent cells from 6-OHDA mediated death. Now, earlier report from our lab had shown that 6-OHDA can induce neuronal apoptosis via activation of a transcription factor called FoxO3a (Sanphui et al 2020). Keeping that in mind, we explored the implications of miR-128 in apoptotic pathways and its effect on FoxO3a activation.…”

The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases

“…MYC and PI3K-AKT signaling cooperatively repress FOXO3a-dependent PUMA expression [ 53 ]. However, chromatin remodeler Brg-associated factor 57 (BAF57), a subunit of SWItch/sucrose non-fermentable (SWI/SNF), executes neuron death in FoxO3a-mediated PUMA expression in cellular models of Parkinson’s disease (PD) [ 54 ]. In addition, autophagy inhibition increases the levels of FOXO3a transcription factor, and promotes PUMA upregulation, thereby increasing apoptosis [ 55 ].…”

“…TRIB3/TRB3 (a target of CHOP) is induced later than CHOP during ER stress [ 98 ], and it can promote PUMA expression in a FOXO3a-dependent manner through the dephosphorylation of AKT in PC-12 cells [ 98 ]. BAF57 executes neuron death in FoxO3a-mediated PUMA expression in cellular models of PD [ 54 ].…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…SIRT1 also is closely associated with the mammalian forkhead transcription proteins [24,55,[193][194][195][196][197]. The induction of autophagy relies upon mammalian FOXO proteins of the O class that have an important relationship to neurodegenerative disorders [40,162,187,198,199]. For example, central nervous system myelination involving oligodendrocyte progenitor cells is believed to be controlled through FoxO1 transcription factors [200] that may impact disease such as multiple sclerosis [201].…”