The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease

A hallmark of Lafora disease (LD), a fatal neurodegenerative disease, is the accumulation of insoluble carbohydrates called Lafora bodies (LBs). LD is caused by mutations in the gene encoding the phosphatase laforin, which reportedly exists solely in vertebrates. We utilized a novel bioinformatics screen to identify laforin orthologs in five protists, Toxoplasma gondii , Eimeria tenella , Tetrahymena thermophila , Paramecium tetraurelia , and Cyanidioschyzon merolae . Strikingly, laforin is absent in all invertebrate organisms, and only exists in vertebrates and these five protists. These protists all evolved from a progenitor red‐alga and all synthesize an insoluble carbohydrate, whose composition closely resembles LBs. Furthermore, we show that Kingdom Plantae, which lacks laforin, possesses a protein with laforin‐like properties called SEX4. Mutations in the Arabidopsis SEX4 gene results in a s tarch ex cess phenotype. We demonstrate that human laforin fully complements the sex4 phenotype, and establish laforin and SEX4 as functional equivalents. Thus, despite the broad evolutionary diversity between vertebrates, plants and protists, laforin and SEX4 conduct a heretofore overlooked conserved function: they regulate the metabolism of “insoluble glycogen”, starch and floridean starch. Finally, we show that this family of phosphatases dephosphorylates insoluble carbohydrates, providing a molecular explanation for the etiology of LD.