Levetiracetam treatment ameliorates LRRK2 pathological mutant phenotype.

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.

• Authors: Mauro Rassu, Alice Biosa, Manuela Galioto, Milena Fais, Paola Sini, Elisa Greggio, Giovanni Piccoli, Claudia Crosio, Ciro Iaccarino
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 23 Issue 12 Pg. 8505-8510 (12 2019) ISSN: 1582-4934 [Electronic] England
• PMID: 31560168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Anticonvulsants
• Membrane Glycoproteins
• Nerve Tissue Proteins
• Levetiracetam
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Topics

• Animals
• Anticonvulsants (pharmacology)
• Cell Line, Tumor
• Cells, Cultured
• Epilepsy (drug therapy, genetics, metabolism)
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (genetics, metabolism)
• Levetiracetam (pharmacology)
• Membrane Glycoproteins (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mutation
• Nerve Tissue Proteins (metabolism)
• Neurites (drug effects, physiology)
• Neurons (drug effects, metabolism, physiology)
• PC12 Cells
• Parkinson Disease (drug therapy, genetics, metabolism)
• Protein Binding
• Rats
• Signal Transduction (drug effects)
• Synaptic Vesicles (metabolism)