Lafora disease is a rare, inevitably fatal, autosomal recessive, progressive myoclonus epilepsy. Being autosomal recessive, the disease is most commonly seen in communities that practice consanguinity. The onset of the disease occurs within the first two decades of life, with an average life span of 10 years following diagnosis (Monaghan & Delanty, 2010). Lafora disease is characterized by myoclonic and tonic-clonic seizures and neurological dysfunction, such as dementia (Monaghan & Delanty, 2010). The hallmark of Lafora disease is the accumulation of inclusions, called Lafora bodies, in the cytoplasm of neuronal somas, the heart, liver, muscles, and other tissues (Roach, 2015). These inclusions are insoluble bodies composed of polyglucosan,
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Laforin is a 331 amino acid protein with a carbohydrate-binding domain (CBD) at its amino terminus. This CBD allows the protein to bind to glycogen and Lafora bodies, with preference given to the latter. Recent studies suggest that the binding of the CBD of laforin to Lafora bodies may be involved in the regulation of aberrant glycogen (Gentry et al., 2005). Upon recognizing a Lafora body, laforin directs a negative feedback pathway to inhibit the accumulation of Lafora bodies by either inhibiting their formation or promoting their destruction (Monaghan & Delanty, 2010). A mutation that results in the lack of laforin and its phosphatase activity leads to an increase in the phosphorylation of glycogen. This causes glycogen to become poorly branched and insoluble. Reduced branching in glycogen leads to the formation and accumulation of polyglucosan inclusions (Tagliabracci et al., 2008). Other studies suggest that laforin is involved in glycogen anabolism by binding to the regulatory subunit, R5/PTG, of protein phosphatase 1, a positive effector of glycogenesis (Gentry et al., 2005). By competing for binding on this subunit or via its phosphatase activity, laforin can promote proper glycogen …show more content…
The first suggests that both laforin and malin function on protein X, the accumulation of which causes Lafora disease, to promote its degradation (Gentry et al., 2005). Laforin could dephosphorylate protein X through its phosphatase activity. This would then trigger protein X to be ubiquitinated by malin and tagged for degradation by a proteasome. Once protein X is degraded, glycogen metabolism could continue to function properly. The second model proposes that laforin acts similarly to a “kamikaze” transcriptional activator (Gentry et al., 2005). Laforin would localize and dephosphorylate substrate X through its phosphatase activity, promoting glycogenesis or the inhibition of aberrant glycogen accumulation. However, this next step would not be able to proceed without first the polyubiquitination and degradation of laforin. Thus, patients with a mutation in the EPM2B gene would develop Lafora disease because proper glycogen metabolism cannot proceed without first the degradation of laforin. Patients with a mutation in the EPM2A gene would develop Lafora disease because of their inability to dephosphorylate substrate X which is needed for proper glycogen metabolism. Both models are plausible in that they take into account the functions and interaction of laforin and malin; however, more studies will need to be done to fully explore the models in detail and
Laforin is a 331 amino acid protein with a carbohydrate-binding domain (CBD) at its amino terminus. This CBD allows the protein to bind to glycogen and Lafora bodies, with preference given to the latter. Recent studies suggest that the binding of the CBD of laforin to Lafora bodies may be involved in the regulation of aberrant glycogen (Gentry et al., 2005). Upon recognizing a Lafora body, laforin directs a negative feedback pathway to inhibit the accumulation of Lafora bodies by either inhibiting their formation or promoting their destruction (Monaghan & Delanty, 2010). A mutation that results in the lack of laforin and its phosphatase activity leads to an increase in the phosphorylation of glycogen. This causes glycogen to become poorly branched and insoluble. Reduced branching in glycogen leads to the formation and accumulation of polyglucosan inclusions (Tagliabracci et al., 2008). Other studies suggest that laforin is involved in glycogen anabolism by binding to the regulatory subunit, R5/PTG, of protein phosphatase 1, a positive effector of glycogenesis (Gentry et al., 2005). By competing for binding on this subunit or via its phosphatase activity, laforin can promote proper glycogen …show more content…
The first suggests that both laforin and malin function on protein X, the accumulation of which causes Lafora disease, to promote its degradation (Gentry et al., 2005). Laforin could dephosphorylate protein X through its phosphatase activity. This would then trigger protein X to be ubiquitinated by malin and tagged for degradation by a proteasome. Once protein X is degraded, glycogen metabolism could continue to function properly. The second model proposes that laforin acts similarly to a “kamikaze” transcriptional activator (Gentry et al., 2005). Laforin would localize and dephosphorylate substrate X through its phosphatase activity, promoting glycogenesis or the inhibition of aberrant glycogen accumulation. However, this next step would not be able to proceed without first the polyubiquitination and degradation of laforin. Thus, patients with a mutation in the EPM2B gene would develop Lafora disease because proper glycogen metabolism cannot proceed without first the degradation of laforin. Patients with a mutation in the EPM2A gene would develop Lafora disease because of their inability to dephosphorylate substrate X which is needed for proper glycogen metabolism. Both models are plausible in that they take into account the functions and interaction of laforin and malin; however, more studies will need to be done to fully explore the models in detail and