title: PTG protein depletion rescues malin-deficient Lafora disease in mouse.
abstract: Ubiquitin ligases regulate quantities and activities of target proteins, often pleiotropically. The malin ubiquitin E3 ligase is reported to regulate autophagy, the misfolded protein response, microRNA silencing, Wnt signaling, neuronatin-mediated endoplasmic reticulum stress, and the laforin glycogen phosphatase. Malin deficiency causes Lafora disease, pathologically characterized by neurodegeneration and accumulations of malformed glycogen (Lafora bodies). We show that reducing glycogen production in malin-deficient mice by genetically removing PTG, a glycogen synthesis activator protein, nearly completely eliminates Lafora bodies and rescues the neurodegeneration, myoclonus, seizure susceptibility, and behavioral abnormality. Glycogen synthesis downregulation is a potential therapy for the fatal adolescence onset epilepsy Lafora disease.
authors.affiliation: Program in Genetics and Genome Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Turnbull
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Epp
authors.forename: Danielle
authors.initials: D
authors.lastname: Goldsmith
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Zhao
authors.forename: Nela
authors.initials: N
authors.lastname: Pencea
authors.forename: Peixiang
authors.initials: P
authors.lastname: Wang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Ackerley
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003213:Conditioning, Psychological; D015536:Down-Regulation; D005239:Fear / Q000523:psychology; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D020192:Lafora Disease / Q000201:enzymology* / Q000523:psychology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D009207:Myoclonus / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D018696:Neuroprotective Agents / Q000378:metabolism; D058225:Plaque, Amyloid; D012640:Seizures / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; C104748:Ppp1r3c protein, mouse; D006003:Glycogen; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D006006:Glycogen Synthase