Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons

Mori, Mayra; Burgess, Daniel L.; Gefrides, Lisa A.; Foreman, Perry J.; Opferman, Joseph T.; Korsmeyer, Stanley J.; Cavalheiro, Ésper A.; Naffah-Mazzacoratti, Maria da Graça; Noebels, Jeffrey L.

doi:10.1038/sj.cdd.4401483

Cited by 43 publications

(43 citation statements)

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“…It has been proposed that the neuroprotective effects of ATF5 are mediated by the transcriptional induction of some proteins with a neuroprotective effect, such as Hsp27, Bcl2 and Mcl1 [58][59][60][61]. Likewise, in our study, we found a significant up-regulation in mcl1, which was also up-regulated in other models of status epilepticus, such as pilocarpine administration in rodents [62].…”

Section: Discussionsupporting

confidence: 82%

“…At the same time, other genes showed similar changes in gene expression profiles between the two genotypes, including bag3, mcl1, traf2 and bcl10. Interestingly, these genes encode proteins that confer antiapoptotic neuroprotection, which could account for the increase in expression in both WT and lpr mice after KA treatment [62]. Therefore, our results suggest neuroprotective effects in lpr mice after KA administration based on genes that are not activated in this model.…”

Section: Discussionmentioning

confidence: 67%

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Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

et al. 2014

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The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT 2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the upregulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 67%

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

et al. 2014

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“…In contrast, AUDA-treated SHRSP had only 1 gene up-regulated Ն2-fold and 11 Ն1.5-fold in comparison with WKY ( Figure 5, C and E; and Table 1). Furthermore, AUDA reduced gene expression of 39 apoptotic factors Ն1.5-fold and 32 Ն2-fold versus SHRSP vehicle-treated rats ( Figure 5, B 43 and an antioxidant peroxiredoxin 2 (Prdx2) in the WKY animals (Table 1 and Figure 5E). …”

Section: Apoptosismentioning

confidence: 96%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

101

118

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Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive WistarKyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDAtreated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke. Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension, 1 match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis, 2 and protect against ischemia.3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids. 5In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke, 6 and this association could be related to modifications in SEH activity, and thus epoxide catabolism. 7 An alternative strategy that has been used to increase EETs systemically is SEH inhibition. 1 We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.8 Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO)

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“…However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival.…”

mentioning

confidence: 99%

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Short-term proteasome inhibition has been shown to prevent neuronal apoptosis. However, the key pro-survival proteins that must be degraded for triggering neuronal death are mostly unknown. Here, we show that Mcl-1, an anti-apoptotic Bcl-2 family member, is degraded by the proteasome during neuronal apoptosis. Using primary cultures of cerebellar granule neurons deprived of serum and KCl, we found that ubiquitination and proteasomal degradation of Mcl-1 depended on its prior phosphorylation by GSK3, providing the first insight into post-translational regulation of Mcl-1 in neurons. In a previous study, we have reported that the E3 ubiquitin-ligase Trim17 is both necessary and sufficient for neuronal apoptosis. Here, we identified In the nervous system, apoptosis plays a critical role both during development and in neurodegenerative diseases. 1 In many neuronal types, apoptosis is triggered through the intrinsic pathway of caspase activation that involves the release of cytochrome c from mitochondria. The proteins of the Bcl-2 family, that comprises both anti-apoptotic (Bcl-2, Bcl-x L , Mcl-1y) and pro-apoptotic members (Bax, Bak, Bimy), play an essential role in the regulation of apoptosis by controlling the integrity of the outer mitochondrial membrane and the release of apoptogenic factors such as cytochrome c. 2 Amongst the anti-apoptotic proteins of the Bcl-2 family, Mcl-1 (Myeloid cell leukemia 1) is characterized by a short half-life. 3 Its rapid degradation by the proteasome has been shown to be required for initiation of the apoptotic cascade in several cell lines. [4][5][6][7] For a long time, little attention was paid to a potential role for Mcl-1 in the nervous system because initial studies did not detect it in neurons. However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival. Nevertheless, post-translational regulation of Mcl-1 has never been studied in neurons.In the present study, we report for the first time that Mcl-1 is degraded by the proteasome during neuronal apoptosis. We found that Mcl-1 degradation depended on its prior phosphorylation by glycogen synthase kinase 3 (GSK3), in primary cultures of CGNs deprived of serum and KCl. This phosphorylation of Mcl-1 favored its physical interaction with Trim17, a novel E3 ubiquitin-ligase involved in neuronal apoptosis. Moreover, our present data provide evidence that Trim17 contributes to the ubiquitination and the proteasomal degradation of Mcl-1 in neurons. As such, we define a novel molecular mechanism for regulation of Mcl-1 and initiation of apoptosis. ResultsMcl-1 is degraded by the proteasome during...

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Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons

Cited by 43 publications

References 54 publications

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

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