期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 7, 页码 906-917出版社
WILEY
DOI: 10.15252/emmm.201707608
关键词
glycogen chain length; glycogen phosphorylation; Lafora disease; laforin; malin
资金
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) [P01 NS097197]
- NHMRC CJ Martin Fellowship [GNT1092451]
Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss-of-function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase-inactive laforin rescues the laforin-deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin-or malin-deficient mouse lines expressing phosphatase-inactive laforin. We find that: (i) in laforindeficient mice, phosphatase-inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin-deficient mice, phosphatase-inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD.
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