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Review
. 2022 Apr;178(4):315-325.
doi: 10.1016/j.neurol.2021.06.006. Epub 2021 Jul 21.

Lafora disease: Current biology and therapeutic approaches

S Mitra  1 , E Gumusgoz  1 , B A Minassian  2
Affiliations
Review

Lafora disease: Current biology and therapeutic approaches

S Mitra et al. Rev Neurol (Paris). 2022 Apr.

Abstract

The ubiquitin system impacts most cellular processes and is altered in numerous neurodegenerative diseases. However, little is known about its role in neurodegenerative diseases due to disturbances of glycogen metabolism such as Lafora disease (LD). In LD, insufficiently branched and long-chained glycogen forms and precipitates into insoluble polyglucosan bodies (Lafora bodies), which drive neuroinflammation, neurodegeneration and epilepsy. LD is caused by mutations in the gene encoding the glycogen phosphatase laforin or the gene coding for the laforin interacting partner ubiquitin E3 ligase malin. The role of the malin-laforin complex in regulating glycogen structure remains with full of gaps. In this review we bring together the disparate body of data on these two proteins and propose a mechanistic hypothesis of the disease in which malin-laforin's role to monitor and prevent over-elongation of glycogen branch chains, which drive glycogen molecules to precipitate and accumulate into Lafora bodies. We also review proposed connections between Lafora bodies and the ensuing neuroinflammation, neurodegeneration and intractable epilepsy. Finally, we review the exciting activities in developing therapies for Lafora disease based on replacing the missing genes, slowing the enzyme - glycogen synthase - that over-elongates glycogen branches, and introducing enzymes that can digest Lafora bodies. Much more work is needed to fill the gaps in glycogen metabolism in which laforin and malin operate. However, knowledge appears already adequate to advance disease course altering therapies for this catastrophic fatal disease.

Keywords: E3 ubiquitin ligase; Gene therapy; Lafora disease; Laforin; Malin.

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Figures

Figure 1.
Figure 1.. Hypothetical role of the laforin-malin complex in glycogen metabolism.
An unknown kinase phosphorylates a pre-existing overly long and poorly branched glycogen chain formed due to occasional local imbalance in glycogen synthase-glycogen branching enzyme activities (1). Laforin-malin is attracted to and docks on this overlong chain (boxed) via laforin’s carbohydrate binding domain (2). Malin ubiquitinates and degrades glycogen synthase or glycogen synthase activating proteins such as protein phosphatase-1α (3). Laforin removes the phosphate (4) allowing chain re-shortening by glycogen phosphorylase (not shown in the picture) (5). Finally, malin ubiquitinates and removes laforin. The end result is a corrected chain with restoration of structural integrity and mitigation of precipitation of the glycogen molecule. Note: Steps 3–5 are shown only with the long glycogen chain.
Figure 2.
Figure 2.. Overview of therapeutic strategies in Lafora disease.
Therapeutic approaches to LD can be classified into two main groups. The first group aims to prevent or arrest the disease progression by targeting glycogen synthase or replacing EPM2A and EPM2B genes. The second group of therapeutics aims to alleviate the existing disease by degrading Lafora bodies and improving LD related neuroinflammation.
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References

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Web Reference:

    1. The Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database: http://projects.tcag.ca/lafora/

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