Laforin in autophagy: A possible link between carbohydrate and protein in Lafora disease?

Abstract

The progressive myoclonus epilepsy of Lafora disease (LD) is a fatal form of neurodegenerative disorder associated with progressive intellectual decline and ataxia in addition to epilepsy. The disease can be caused by defects in the EPM2A gene encoding laforin phosphatase or the NHLRC1 gene encoding malin ubiquitin ligase. Laforin and malin function together as a complex in the ubiquitin-proteasome system, and hence defects in proteolytic processes are thought to underlie some of the symptoms in LD. One of the pathological hallmarks of LD is the presence of cytoplasmic polyglucosan inclusions, the Lafora bodies. While Lafora bodies are known as a lesser branched form of glycogen with high phosphate content, a physiological basis for their genesis in the cytoplasm was not well understood. Recently it was shown in a mouse model for LD that loss of laforin inhibits autophagosome formation, suggesting that laforin plays a critical role in autophagosome biogenesis. The polyglucosan inclusions could be one of the substrates of autophagy, and loss of laforin might affect their sequestration into autophagosomes leading to their aggregation as Lafora bodies. Thus, laforin's proposed role in autophagy suggests a possible link between the proteolytic system and the polyglucosan inclusions in LD. © 2010 Landes Bioscience.