title: Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway.
abstract: Lafora disease (LD) is an autosomal recessive, progressive, and fatal form of a neurodegenerative disorder characterized by the presence of Lafora polyglucosan bodies. LD is caused by defects in either the laforin protein phosphatase or the malin E3 ubiquitin ligase. Laforin and malin were shown play key roles in proteolytic processes, unfolded stress response, and glycogen metabolism. Therefore, the LD proteins laforin and malin are thought to function as pro-survival factors and their loss thus could result in neurodegeneration. To understand the molecular pathway leading to the cell death in LD, in the present study, we investigated the possible role of LD proteins in the p53-mediated cell death pathway. We show that loss of laforin or malin results in the increased level and activity of p53, both in cellular and animal models of LD, and that this is primarily due to the increased levels of Hipk2, a proapoptotic activator of p53. Overexpression of laforin or malin confers protection against Hipk2-mediated cell death by targeting the Hipk2 to the cytoplasmic compartment. Taken together, our study strengthens the notion that laforin and malin are pro-survival factors, and that the activation of Hipk2-p53 cell death pathway might underlie neurodegeneration in LD.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
authors.forename: Mamta
authors.initials: M
authors.lastname: Upadhyay
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Bhadauriya
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India; Center of Excellence for Chemical Biology, Indian Institute of Technology, Kanpur, India. Electronic address: sganesh@iitk.ac.in.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
keywords: Cell death pathway; Epilepsy; Neurodegeneration; Post-translational modification