Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a

Abstract

Intracellular transport, processing and stability of mRNA play critical roles in the functional physiology of the cell and defects in these processes are thought to underlie the pathogenesis in a number of neurodegenerative disorders. One of the cellular sites that regulate the mRNA half-life is the processing bodies, the dynamic cytoplasmic structures that represent the non-translating mRNA and the ribonucleoprotein complex that also control the decapping and translation of mRNA. In the present study we explored the possible role of malin E3 ubiquitin ligase in the mRNA decay pathway via the processing bodies. Defects in malin are associated with Lafora disease (LD)-a neurodegenerative disorder characterized by myoclonus seizures. We show here that malin is recruited to the processing bodies and that malin regulates the recruitment of mRNA decapping enzyme Dcp1a by promoting its degradation via the ubiquitin proteasome system. Depletion of malin results in elevated levels of Dcp1a and an altered microRNA-mediated gene silencing activity. Our study suggests that malin is one of the critical regulators of processing bodies and that defects in the mRNA processing might underlie some of the disease symptoms in LD.

Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway

“…The pro-apoptotic function of p53 is regulated by multiple factors and HIPK2 is the one that activate p53 via post-translation modification leading to the conformational stability and activity of the latter [14,15]. Consistent with this model, the cytoplasmic HIPK2 was not able to activate p53, suggesting the presence of other factors that regulate subcellular localization of HIPK2 and its activity [20,35]. CHIP is one of such factors and is known to modulate the HIPK2ep53 interaction in stress-dependent manner [23].…”

“…We and others have previously reported a role for Lafora disease proteins laforin and malin in cellular stress response [9,29,30], proteolytic processes [7,8,31], glucose metabolism [32e34] and RNA metabolism [35]. In this report, we attempt to propose a link for the LD proteins in the HIPK2-p53-mediated cell death pathway.…”

Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

“…The mRNA decapping enzyme DCP1α plays a fundamental role in the miRNA-mediated suppression of translation48. miRNA-mediated gene silencing activity is usually coupled with the elevated expression of DCP1α49. However, Ago2 and DCP1α decreased microscopically visible association following treatment with DCB-3503 or CHX (Fig.…”

PDE7B, NMBR and EPM2A Variants and Schizophrenia: A Case-Control and Pharmacogenetics Study

“…The EPM2A gene, which is located on chromosome 6q24, encodes for a cytoplasmically active enzyme, the laforin phosphatase [39]. Autosomal recessive inheritance of mutations in this gene gives rise to the accumulation of an unmetabolized form of glycogen, polyglucosans, which is associated with Lafora disease [25]. Laforin is part of a complex of proteins associated with glycogen and may have a role in regulating its metabolism [24].…”

“…Autosomal recessive inheritance of mutations in this gene gives rise to the accumulation of Lafora bodies, which consist of an unmetabolized form of glycogen, polyglucosans, which is associated with progressive neurological deterioration [25]. Several studies hypothesized a possible role of glycogen metabolism in SCZ susceptibility as well as the antipsychotic mechanism of action [26,27,28].…”