Laforin

Laforin is a protein phosphatase involved in glycogen metabolism and neuronal function. Specifically, it is a dual-specificity phosphatase, meaning it can remove phosphate groups from both serine/threonine and tyrosine residues on proteins. Laforin is encoded by the EPM2A gene.

Function:

The primary known function of laforin is to dephosphorylate glycogen. It plays a crucial role in preventing the accumulation of abnormally structured, poorly branched glycogen, often referred to as polyglucosan bodies. By removing phosphate groups, laforin helps to maintain proper glycogen structure and solubility. It interacts with and dephosphorylates proteins involved in glycogen metabolism, including glycogen synthase. Laforin also appears to play a role in regulating protein aggregation and degradation pathways, helping to prevent the buildup of toxic protein aggregates within cells.

Clinical Significance:

Mutations in the EPM2A gene, leading to defects in laforin, are the primary cause of Lafora disease (LD), also known as progressive myoclonus epilepsy type 2 (EPM2). Lafora disease is a rare, autosomal recessive neurodegenerative disorder characterized by progressive myoclonus epilepsy, cognitive decline, ataxia, and visual disturbances. The disease onset typically occurs in adolescence. The hallmark of Lafora disease is the presence of Lafora bodies, insoluble aggregates of poorly branched glycogen, found in the brain, muscle, liver, and skin.

Structure:

Laforin is a protein composed of two distinct domains: a carbohydrate-binding domain (CBD) and a dual-specificity phosphatase domain (DSP). The CBD allows laforin to bind to glycogen and other carbohydrate structures. The DSP domain contains the catalytic site responsible for phosphatase activity.

Further Research:

Research continues to explore the precise mechanisms by which laforin regulates glycogen metabolism and neuronal function, as well as potential therapeutic strategies for Lafora disease. This includes investigation into Laforin's interaction with other proteins, its role in autophagy and the unfolded protein response, and the development of therapies targeting Lafora body formation.