Genomes and Genes
Molecular Pathological Mechanism & Potential Therapeutics of Lafora Disease
Principal Investigator: YAN NONE LIU
Abstract: DESCRIPTION (provided by applicant): Lafora disease (LD) is an autosomal recessive and incurable disease with characters of progressive myoclonus epilepsy (PME), severe neurological deterioration, and the accumulation of starch-like glycogen inclusion bodies (LB) mainly in the brain, muscle, and liver. Defects in two genes: EPM2A, which encodes a dual specificity phosphatase named Laforin and NHLRC, which encodes an E3 ligase named Malin, are identified to be directly linked to the disease. However, the molecular pathological cause of LD is unknown. Two common pathological causes for developing neurodegenerative diseases are diverse abnormal aggregates formed inside or outside of affected neuronal cells and endoplasmic reticulum (ER) stress-induced neuronal apoptosis. We found that the homodimer of Laforin is critical for its optimal phosphatase activity and the majority of missense mutants carried by LD patients impair the mutants'ability to form homodimer, consequently loosing phosphatase activity as well. These mutants elicit unfolded protein response (UPR) when expressed in non-neuronal or neuronal cells;however, they are inefficiently degraded by proteasome and are retained intracellularly as detergent-resistant ubiquitin-positive aggregates around nuclei. Once expressed in neuronal cells, mutants make the cells vulnerable to death induced by ER stressor thapsigargin. In contrast to the mutants, wild type Laforin, predominantly located in the ER, functions as a guardian sensing ER stress and resists ER stress-induced cell death. Therefore, the aggregates and ER stress that are initiated by the mutation in EPM2A gene could be two major pathological causes for LD development. By molecular genetic approaches of overexpression, tetrocycline-regulation, knockdown, and knockout of Epm2a in vitro and in vivo in Epm2a knockout mouse model, we will delineate the molecular mechanism of LD. Based on our preliminary data in vitro and in vivo, we hypothesize that Laforin functions in mobilizing endogenous glucose for emergent supply, preventing glycogen accumulation, easing ER stress, and protecting cells from stress-induced apoptosis. The molecular mechanism of LD is likely that EPM2A mutant-triggered ER stress in combination with loss of Laforin protective role in ER stress, preventive role in glycogen accumulation cause progressive epilepsy and severe neuronal degeneration. These findings provide very important insight not only for developing therapeutic agents for the treatment of the so far incurable LD patients but also for extending Laforin study in other stress- induced diseases such as stresses of hypoglycemia, ischemia, and hypoxia. PUBLIC HEALTH RELEVANCE: This research proposal will test the hypothesis that Epm2a mutant-formed aggregate, mutant triggered- endoplasmic reticulum (ER) stress, loss of wild type Epm2a (laforin) protective role in ER stress, and defect in laforin preventive role in glycogen accumulation and neuronal cell apoptosis are major pathologic causes for development of Lafora disease (LD). Our preliminary data demonstrated that laforin senses ER stress, mobilizes endogenous glucose for emergent glucose supply, prevents glycogen accumulation, and protects cells from stress-induced apoptosis. Our proposal will provide very important evidences for delineating the molecular mechanism of LD by molecular genetic approach in vitro and in vivo in Epm2a knockout mouse model. The protective role of laforin in ER stress and possibly other stresses such as hypoglycemia, ischemia, and hypoxia, will extend laforin function to other stress-induced diseases. Therefore, the proposed study could establish new protective rationales to push forward laforin study in other stress-related disorders. Knowledge gained from this project could greatly improve the care of Lafora patients and provide very important insight for developing therapeutic agents for the treatment of the so far incurable LD patients.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
- Laforin is required for the functional activation of malin in endoplasmic reticulum stress resistance in neuronal cellsLi Zeng
Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
FEBS J 279:2467-78. 2012..These results reveal that a functional laforin-malin complex plays a critical role in disrupting Lafora bodies and relieving ER stress, implying that a causative pathogenic mechanism underlies their deficiency in Lafora disease...
- Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora diseaseErica Tiberia
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
J Biol Chem 287:25650-9. 2012..We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen...
- Early-onset Lafora body diseaseJulie Turnbull
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
Brain 135:2684-98. 2012..The results to date suggest that PRDM8, the early-onset Lafora body disease protein, regulates the cytoplasmic quantities of the Lafora disease enzymes...
- Laforin prevents stress-induced polyglucosan body formation and Lafora disease progression in neuronsYin Wang
Section of General Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Mol Neurobiol 48:49-61. 2013..We propose that deficiency in the degradative phase of this metabolism, leading to LB accumulation and resultant seizure predisposition and neurodegeneration, underlies LD...
- Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylaseYan Liu
Center for Cancer and Immunology Research, Children s National Medical Center and George Washington University, 111 Michigan Avenue NW, Washington, DC, 20010, USA
Mol Neurobiol 49:645-57. 2014..Mutations in AGL1 or GPBB may cause diseases related to PB accumulation. ..
- Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytesYin Wang
Department of Surgery, Division of Immunotherapy, Section of General Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
J Cell Sci 124:3568-80. 2011..These features of SERCA2 and its mutants establish a mechanistic base to further elucidate the molecular pathogenesis underlying acantholysis and dyskeratosis in DD...