ABSTRACT
Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in the affected tissues including the brain. LD can be caused by defects either in the EPM2A gene coding for the laforin protein phosphatase or the NHLRC1 gene coding for the malin ubiquitin ligase. Since the clinical symptoms of LD patients representing the two genetic groups are very similar and since malin is known to interact with laforin, we were curious to examine the possibility that the two proteins regulate each other’s function. Using cell biological assays we demonstrate here that (i) malin promotes its own degradation via auto-ubiquitination, (ii) laforin prevents the auto-degradation of malin by presenting itself as a substrate and (iii) malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each other’s stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneity observed in LD.
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16 August 2018
The image of anti-Myc blot of figure 2C (third panel; Malin-Myc [C26S]) was inadvertently used once again for the γ-tubulin loading control of figure 2B.
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Acknowledgements
The authors wish to thank Prof Lih-Shen Chin of Emory University School of Medicine, USA, for providing the mutant ubiquitin construct. This work was supported by a research grant from the Department of Atomic Energy, India, in the form of DAE-SRC Outstanding Research Investigator Award, to SG.
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Corresponding editor: Sarah H Elsea
[Mittal S, Upadhyay M, Singh PK, Parihar R and Ganesh S 2015 Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease. J. Biosci.] DOI 10.1007/s12038-015-9570-0
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Mittal, S., Upadhyay, M., Kumar Singh, P. et al. Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease. J Biosci 40, 863–871 (2015). https://doi.org/10.1007/s12038-015-9570-0
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DOI: https://doi.org/10.1007/s12038-015-9570-0