Calpain-mediated Degradation of Myocyte Enhancer Factor 2D Contributes to Excitotoxicity by Activation of Extrasynaptic N-Methyl-d-aspartate Receptors

Wei, Gengze; Yin, Yulong; Li, Wenming; Bito, Haruhiko; She, Hua; Mao, Zixu

doi:10.1074/jbc.m111.260109

Cited by 12 publications

(10 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Together, these findings indicate that CMA preferentially degrades oxidized and nonfunctional MEF2D. Since proteolytic cleavage of MEF2D has been shown to generate a dominant negative fragment (17,38,39), an accumulation of non-functional MEF2D may lead to its aberrant processing and the generation of fragments that are detrimental to neuronal viability. Based on all these observations, we propose a model in which moderate oxidative stress activates CMA and removes oxidized non-functional MEF2D.…”

Section: Oxidation Cma and Mef2d In Pdmentioning

confidence: 96%

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

She

et al. 2014

Antioxidants & Redox Signaling

Self Cite

View full text Add to dashboard Cite

Aims: Dysfunction of myocyte enhancer factor 2D (MEF2D), a key survival protein and transcription factor, underlies the pathogenic loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Both genetic factors and neurotoxins associated with PD impair MEF2D function in vitro and in animal models of PD. We investigated whether distinct stress conditions target MEF2D via converging mechanisms. Results: We showed that exposure of a DA neuronal cell line to 6-hyroxydopamine (6-OHDA), which causes PD in animals models, led to direct oxidative modifications of MEF2D. Oxidized MEF2D bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of MEF2D. Importantly, 6-OHDA induced MEF2D oxidation and increased LAMP2A in the substantia nigra pars compacta region of the mouse brain. Consistently, the levels of oxidized MEF2D were much higher in postmortem PD brains compared with the controls. Functionally, reducing the levels of either MEF2D or LAMP2A exacerbated 6-OHDA-induced death of the DA neuronal cell line. Expression of an MEF2D mutant that is resistant to oxidative modification protected cells from 6-OHDA-induced death. Innovation: This study showed that oxidization of survival protein MEF2D is one of the pathogenic mechanisms involved in oxidative stress-induced DA neuronal death. Conclusion: Oxidation of survival factor MEF2D inhibits its function, underlies oxidative stress-induced neurotoxicity, and may be a part of the PD pathogenic process. Antioxid. Redox Signal. 20, 2936Signal. 20, -2948

show abstract

Section: Oxidation Cma and Mef2d In Pdmentioning

confidence: 96%

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

She

et al. 2014

Antioxidants & Redox Signaling

Self Cite

View full text Add to dashboard Cite

show abstract

“…Calpains are ubiquitously expressed in the CNS, and a clear rise in their levels has been observed in models of both transient focal and global ischaemia [272,280]. As well, activated calpains have been associated with damage to a variety of proteins [10,241,254], and calpain inhibitors have been found to provide a measure of protection in both culture [10] and in vivo models of ischaemia [12].…”

Section: Pathogenesismentioning

confidence: 99%

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

Pavlov¹,

Mielke²

2012

Protein Phosphorylation in Human Health

View full text Add to dashboard Cite

“…In contrast, the excessive activation of extrasynaptic NMDAR induces signaling pathways promoting transcription of pro-apoptotic genes and mitochondrial injury, contributing to excitotoxic cell death (Stanika et al, 2009;Leveille et al, 2010;Kaufman et al, 2012;Wroge et al, 2012). Moreover, extrasynaptic NMDAR activity induces calpainmediated cleavage of Myocyte enhancer factor 2 (MEF2), glutamic acid decarboxylase (GAD65/67), Fodrin, NCX3, and STEP (Xu et al, 2009a,b;Monnerie et al, 2010;Wei et al, 2012). activation of calpains by the intracellular calcium overload in brain ischemia and in excitotoxic conditions (Camins et al, 2006;Bevers and Neumar, 2008) leads to the cleavage of plasma membrane proteins (Lu et al, 2000;Neumar et al, 2001;Rong et al, 2001;Yuen et al, 2007;Gomes et al, 2012), synaptic vesicle proteins Lobo et al, 2011), transporters (Bano et al, 2005;Pottorf et al, 2006), mitochondrial proteins (Takano et al, 2005) and many other substrates (Bevers and Neumar, 2008).…”

Section: Intracellular Calcium Overloadmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

View full text Add to dashboard Cite

A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

show abstract

Calpain-mediated Degradation of Myocyte Enhancer Factor 2D Contributes to Excitotoxicity by Activation of Extrasynaptic N-Methyl-d-aspartate Receptors

Cited by 12 publications

References 41 publications

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Contact Info

Product

Resources

About