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https://www.ias.ac.in/article/fulltext/jbsc/040/05/0863-0871

Epilepsy; locus heterogeneity; post-translational modification; protein-protein interaction

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 𝑁𝐻𝐿𝑅𝐶𝐼 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 others function. Using cell biological assays we demonstrate here that

1. malin promotes its own degradation via auto-ubiquitination,

2. laforin prevents the auto-degradation of malin by presenting itself as a substrate and

3. malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each others stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneityobserved in LD.

Shuchi Mittal^{1 2} Mamta Upadhyay¹ Pankaj Kumar Singh^{1 3} Rashmi Parihar¹ Subramaniam Ganesh¹

1. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India
2. Harvard Medical School and Brigham and Women s Hospital, Cambridge, USA
3. Institut de Génétique et de Biologic Mole'culaire et Cellulare (IGBMC), Illkirch, France

Published

December 2015

Manuscript received

7 June 2015

Accepted

27 August 2015