{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The EPM2A gene encodes laforin, a unique dual‐specificity phosphatase characterized by an N‐terminal carbohydrate‐binding module that enables direct interaction with glycogen. Laforin’s principal role is to “edit” glycogen by dephosphorylating its glucan chains; this activity is essential to maintain normal glycogen structure and solubility by preventing aberrant phosphorylation that would otherwise distort branching and promote the formation of insoluble polyglucosan deposits (Lafora bodies) – the pathological hallmark of Lafora disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its glucan phosphatase activity, laforin functions as an adaptor protein by forming a functional complex with the E3 ubiquitin ligase malin. This partnership regulates multiple aspects of glycogen metabolism—for example, by targeting positive regulators of glycogen synthesis such as PTG and glycogen synthase for ubiquitination and degradation—as well as modulating the activity of kinases like GSK3β; through these actions, laforin contributes to feedback loops that fine‐tune both glycogen production and its structural properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, laforin is implicated in broader cellular homeostasis by influencing the cell’s response to diverse stresses. Loss or malfunction of laforin not only leads to glycogen hyperphosphorylation and insolubility but also results in impaired autophagy and heightened endoplasmic reticulum stress, events that contribute to neurodegeneration. Laforin has even been shown to dephosphorylate Tau, suggesting a role in modulating protein aggregates that are relevant to neurodegenerative processes, and it may function as a tumor suppressor through regulation of key signaling pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these multifaceted functions of laforin demonstrate that EPM2A is central not only to maintaining proper glycogen metabolism—ensuring that glycogen remains appropriately structured and soluble—but also to safeguarding neuronal and cellular integrity under stress. Disruption of laforin’s enzymatic activity, subcellular localization, or interactions with partners such as malin ultimately underpins the pathogenesis of Lafora disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elayne M Chan, Edwin J Young, Leonarda Ianzano, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/11.11.1251"}], "href": "https://doi.org/10.1093/hmg/11.11.1251"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12019206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12019206"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Vincent S Tagliabracci, Julie Turnbull, Wei Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0707952104"}], "href": "https://doi.org/10.1073/pnas.0707952104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18040046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18040046"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Carolyn A Worby, Matthew S Gentry, Jack E Dixon "}, {"type": "b", "children": [{"type": "t", "text": "Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M606117200"}], "href": "https://doi.org/10.1074/jbc.M606117200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16901901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16901901"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Carolyn A Worby, Matthew S Gentry, Jack E Dixon "}, {"type": "b", "children": [{"type": "t", "text": "Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M708712200"}], "href": "https://doi.org/10.1074/jbc.M708712200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18070875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18070875"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yan Liu, Yin Wang, Cindy Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M607778200"}], "href": "https://doi.org/10.1074/jbc.M607778200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16971387"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16971387"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Carmen Aguado, Sovan Sarkar, Viktor I Korolchuk, et al. 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