Novel Model Systems Link Floridean Starch Metabolism to Lafora Disease

  • Gentry, Matthew (PI)

Grants and Contracts Details


The focus of this grant is to determine how laforin, the only phosphatase in Kingdom Animalia with a carbohydrate binding module, regulates changes in glycogen metabolism. Humans develop insoluble aberrant glycogen particles, called Lafora bodies, as a result of an autosomal recessive neurodegenerative disorder known as Lafora disease (LD). LD is the result of loss of function mutations in either the gene that encodes the dual specific phosphatase laforin or the E3 ubiquitin ligase malin. LD is one of five major progressive myoclonus epilepsies (PMEs) and presents as a single seizure in the second decade of the patient's life; this single event is followed by progressive central nervous system degeneration and ends with death within ten years. Laforin is reported as only being conserved among vertebrates; however, laforin orthologs have been identified in five unicellular eukaryotes, including Cyanidioschyzon merolae and Toxoplasma gondii. Furthermore, the biochemical composition of LBs closely resembles that offloridean starch; an insoluble carbohydrate molecule synthesized by the same unicellular eukaryotes that have laforin. Thus, there is a direct correlation between the presence oflaforin and synthesis of floridean starch amongst invertebrates. Additionally, a protein in plants called SEX4 has recently been described that has similar in vitro characteristics as laforin. Plants also produce insoluble carbohydrates in the form of starch. Strikingly, mutations in SEX4 result in a starch excess phenotype, a characteristic very similar to LD. Thus, I propose that a laforin-like activity is involved in degrading insoluble carbohydrates, either to utilize them as an energy source for invertebrates and plants or to protect cellular integrity in mammals, and that laforin's role in these two processes is conserved from plants to invertebrates to humans. This proposal will determine laforin's function in glycogen metabolism.
Effective start/end date9/15/072/28/13


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