Abstract
Mutations in leucine‐rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The LRRK2 physiological and pathological function is still debated. However, different experimental evidence based on LRRK2 cellular localization and LRRK2 protein interactors suggests that LRRK2 may be part and regulate a protein network modulating vesicle dynamics/trafficking. Interestingly, the synaptic vesicle protein SV2A is part of this protein complex. Importantly, SV2A is the binding site of the levetiracetam (LEV), a compound largely used in human therapy for epilepsy treatment. The binding of LEV to SV2A reduces the neuronal firing by the modulation of vesicle trafficking although by an unclear molecular mechanism. In this short communication, we have analysed the interaction between the LRRK2 and SV2A pathways by LEV treatment. Interestingly, LEV significantly counteracts the effect of LRRK2 G2019S pathological mutant expression in three different cellular experimental models. Our data strongly suggest that LEV treatment may have a neuroprotective effect on LRRK2 pathological mutant toxicity and that LEV repositioning could be a viable compound for PD treatment.
Highlights
Approved by the US Food and Drug Administration in the 1999, levetiracetam (LEV) is a widely used drug for the treatment of partial and generalized epilepsy
Different experimental evidence based on leucine‐rich repeat kinase 2 (LRRK2) cellular localization and LRRK2 protein interactors suggests that LRRK2 may be part and regulate a protein network modulating vesicle dynamics/trafficking
Our data strongly suggest that LEV treatment may have a neuroprotective effect on LRRK2 pathological mutant toxicity and that LEV reposi‐ tioning could be a viable compound for Parkinson's disease (PD) treatment
Summary
Marcotulli and colleagues have analysed the effect of LEV on presynaptic proteins level and distribution in the rat cere‐ bral cortex.[10] In this experimental model, the expression of different vesicular proteins is modified upon LEV treatment and LRRK2 is part of this protein network.[10] In addition, SV2A was pulled down from adult mouse brain lysates by the LRRK2 WD40 domain[11] suggesting a their involvement to common cellular pathways. Whether LRRK2 and SV2A have a functional interaction and more important whether they have an opposite or synergistic bio‐ logical effect remain to be explored. To test this hypothesis, we have evaluated the ability of LEV to affect the LRRK2 cellular effects in different experimental models
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