Modulation of Neuronal Survival Factor MEF2 by Kinases in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder due to selective death of neurons in the substantia nigra pars compacta. The cause of cell death remains largely unknown. Myocyte enhancer factor 2 (MEF2) is a group of transcriptional factors required to regulate neuronal development, synaptic plasticity, as well as survival. Recent studies show that MEF2 functions are regulated in multiple subcellular organelles and suggest that dysregulation of MEF2 plays essential roles in the pathogenesis of PD. Many kinases associated with transcription, translation, protein misfolding, autophagy, and cellular energy homeostasis are involved in the neurodegenerative process. Following the first demonstration that mitogen-activated protein kinase p38 (p38 MAPK) directly phosphorylates and activates MEF2 to promote neuronal survival, several other kinase regulators of MEF2s have been identified. These include protein kinase A and extracellular signal regulated kinase 5 as positive MEF2 regulators, and cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β as negative regulators in response to diverse toxic signals relevant to PD. It is clear that MEF2 has emerged as a key point where survival and death signals converge to exert their regulatory effects, and dysregulation of MEF2 function in multiple subcellular organelles may underlie PD pathogenesis. Moreover, several other kinases such as leucine-rich repeat kinase 2 and PTEN-induced putative kinase 1 (PINK1) are of particular interest due to their potential interaction with MEF2.

Interferon‐γ induces leucine‐rich repeat kinase LRRK2 via extracellular signal‐regulated kinase ERK5 in macrophages

“…Another major target of ERK5 indirect transcriptional modulation is a group of transcription factors termed myocyte enhancer factor 2, which have been suggested to play a role in PD (Yin et al . ). The IFN‐γ–ERK5 pathway could also indirectly influence the LRRK2 promotor by inducing transcription factors that in turn activate LRRK2 expression.…”

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

“…Dopaminergic cells are particularly susceptible to oxidative stress (Graham et al, 1978), while neurotrophic and anti-apoptotic factors can confer protection against environmental and genetic risk factors associated with PD pathogenesis (Mangano et al, 2011; Nagahara and Tuszynski, 2011; Rieker et al, 2012; Stahl et al, 2011; Yin et al, 2012). We showed that in cases of increased protection against 6-OHDA-induced death, such as following neuronal RNF11 knockdown, there is an associated increase in expression of (1) antioxidants GSS and SOD1, (2) neurotrophic factor BDNF and (3) anti- apoptotic factor BCL2.…”

Emerging roles for MEF2 transcription factors in memory

“…The regulation of MEF2 activity is complex. MEF2-dependent gene transcription depends not only on the nature of extracellular stimuli (McKinsey et al 2002) but also on the complement of MEF2 isoforms expressed within a cell (including alternatively spliced variants), isoform dimerization, regulated degradation and phosphorylation state (Ornatsky & McDermott 1996;Yin et al 2012). Indeed, phosphorylation and dephosphorylation of MEF2 regulate a large number of processes related to MEF2 function, including modulation of DNA-binding affinity, association with transcriptional coregulators or co-repressors, acetylation and sumoylation, nuclear and cytoplasmic trafficking and caspase-mediated degradation (Heidenreich & Linseman 2004;Li et al 2001;Shalizi et al 2006;Yin et al 2012) (Fig.…”