Lafora disease (LD) is an inherited autosomal recessive progressive myoclonus epilepsy. It typically presents as a single seizure in the second decade of the patient’s life and is followed by progressive neurological deterioration and usually death within ten years of the onset. LD cannot be managed by medication and there is no known cure. Approximately 88% of the LD cases are caused by mutations in either of the two genes encoding for the proteins laforin and malin. The mutations that cause LD in the remaining 12% of the cases are not known. A characteristic of LD is the accumulation of insoluble deposits that contain an aberrant form of glycogen (the major human energy reserve) within muscle and nerve cells. It is hypothesized that these so-called Lafora bodies (LBs) trigger the development of the LD symptoms. Little is known about the mechanisms that lead to LB formation, though. Two different mechanisms have been proposed. Either excessive glycogen phosphorylation or an imbalance between glycogen synthesizing enzymes could result in the accumulation of insoluble LBs. However, up to know the mechanism responsible for glycogen phosphorylation is unknown and the LB structure is only insufficiently characterized.

Gebert Rüf Stiftung was supporting this project because of its innovative strategy for the identification of novel factors involved in Lafora disease formation. The complementary approach applied state-of-the-art analytical techniques and led to a better molecular and biochemical understanding of the disease. It thus paved the way to potentially develop new forms of Lafora disease treatment.

In order to identify novel protein factors involved in LB formation and/or glycogen phosphorylation, we took a proteomics approach. We isolated native LBs from various tissues of a LD mouse model (mice that are deficient in laforin) and identified bound proteins by mass spectrometry. We found a number of proteins known to be involved in glycogen metabolism indicating the feasibility of our approach. Interestingly, we also identified proteins, which were not directly assigned to glycogen metabolism before. These are likely new proteins involved in glycogen phosphorylation, LB formation and/or LD establishment, thus representing new potential targets for LD diagnostics and/or therapy. Our future research will hopefully unravel the in vivo role of these proteins with particular emphasis on their function in Lafora disease.

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