start-ver=1.4
cd-journal=joma
no-vol=2
cd-vols=
no-issue=9
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2016
dt-pub=20160908
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=S-nitrosylation of laforin inhibits its phosphatase activity and is implicated in Lafora disease
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Recently, the relation between S-nitrosylation by nitric oxide (NO), which is over�produced under pathological conditions and neurodegenerative diseases, includingAlzheimer’s and Parkinson’s diseases, has become a focus of attention. Although mostcases of Parkinson’s disease are known to be caused by mutations in the Parkin gene, arecent finding has indicated that S-nitrosylation of Parkin affects its enzymatic activityand leads to the Parkinsonian phenotype. Therefore, it is important to understand thefunction of S-nitrosylated proteins in the pathogenesis of neurodegenerative diseases.Lafora disease (LD, OMIM 254780) is a neurodegenerative disease characterized by theaccumulation of insoluble glucans called Lafora bodies (LBs). LD is caused by mutationsin genes that encode the glucan phosphatase, Laforin, or the E3 ubiquitin ligase, Malin.In this study, we hypothesized that LD may be caused by S-nitrosylation of Laforin,which is similar to the finding that Parkinson’s disease is caused by S-nitrosylation ofParkin. To test this hypothesis, we first determined whether Laforin was S-nitrosylatedusing a biotin switch assay, and compared the three main functions of unmodified andS-nitrosylated Laforin, namely glucan- and Malin-binding activity and phosphataseactivity. Furthermore, we examined whether the numbers of LBs were changed byNO in the cells expressing wild-type Laforin. Here, we report for the first time thatS-nitrosylation of Laforin inhibited its phosphatase activity and that LB formation wasincreased by an NO donor. Our results suggest a possible hypothesis for LD pathogenesis; that is, the decrease in phosphatase activity of Laforin by S-nitrosylation leads toincreased LB formation. Therefore, LD may be caused not only by mutations in theLaforin or Malin genes, but also by the S-nitrosylation of Laforin.

en-copyright=
kn-copyright=

en-aut-name=ToyotaRikako
en-aut-sei=Toyota
en-aut-mei=Rikako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=HonjoYasuko
en-aut-sei=Honjo
en-aut-mei=Yasuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=ImajoRisa
en-aut-sei=Imajo
en-aut-mei=Risa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=SatohAyano
en-aut-sei=Satoh
en-aut-mei=Ayano
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

affil-num=1
en-affil=
kn-affil=

affil-num=2
en-affil=Graduate School of Natural Science and Technology, Okayama University; Research Institute for Radiation Biology and Medicine, Hiroshima University
kn-affil=

affil-num=3
en-affil=Graduate School of Natural Science and Technology, Okayama University; Research Institute for Radiation Biology and Medicine, Hiroshima University
kn-affil=

affil-num=4
en-affil=Graduate School of Natural Science and Technology, Okayama University; Research Institute for Radiation Biology and Medicine, Hiroshima University
kn-affil=
en-keyword=S-Nitrosylation Of Laforin
kn-keyword=S-Nitrosylation Of Laforin
en-keyword=Post-Translational Modification 
kn-keyword=Post-Translational Modification 
en-keyword=Nitrosylation
kn-keyword=Nitrosylation
en-keyword=Phosphatase
kn-keyword=Phosphatase
en-keyword=Glucan-Binding
kn-keyword=Glucan-Binding
END