PARKINSON’S DISEASE AND VESICULAR TRAFFICKING: FROM MOLECULAR PATHOLOGICAL MECHANISM TO A THERAPEUTIC OPTION

Parkinson's disease (PD) is a neurological disorder mainly characterized by the progressive death of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Mutations in LRRK2 are the main genetic cause of PD. Several experimental evidence suggest a critical role of LRRK2 in the control of vesicle trafficking, and alteration of synaptic vesicle trafficking seems a common pathological mechanism in PD. In my PhD thesis, I have studied the molecular mechanisms by which LRRK2 affects the modulation of vesicle dynamics/trafficking by different experimental approaches First of all, I have analysed the molecular interaction between LRRK2 and SV2A. SV2A, a synaptic vesicle protein, is the binding site of Levetiracetam (LEV), a compound widely used in human therapy for the treatment of epilepsy. Binding of LEV to SV2A reduces neuronal firing through modulation of vesicle trafficking, albeit by an unclear molecular mechanism. Interestingly, LEV significantly counteracts the effect of LRRK2 G2019S pathological mutant in three different experimental cell models. Our data strongly suggest that LEV treatment may have a neuroprotective effect on the toxicity of the LRRK2 pathological mutant. Our attention also focused on another actor involved in the regulation of vesicular trafficking: Sec8. Sec8 is a member of the exocyst complex, an evolutionarily conserved multisubunit protein complex mainly involved in the transport of secretory vesicles to the plasma membrane. Our experimental results indicate that LRRK2 interact with Sec8 and that LRRK2 by its kinase activity regulates the exocyst subunit assembly. Moreover, the overexpression of Sec8 significantly corrects the pathological effect of the LRRK2 G2019S mutant. Our results strongly suggest an interesting molecular mechanism by which LRRK2 might modulate vesicle trafficking. Finally, all these results may have important implications for the definition of new therapeutic approaches/targets for PD treatment.

Parkinson's disease (PD) is a neurological disorder mainly characterized by the progressive death of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Mutations in LRRK2 are the main genetic cause of PD. Several experimental evidence suggest a critical role of LRRK2 in the control of vesicle trafficking, and alteration of synaptic vesicle trafficking seems a common pathological mechanism in PD. In my PhD thesis, I have studied the molecular mechanisms by which LRRK2 affects the modulation of vesicle dynamics/trafficking by different experimental approaches First of all, I have analysed the molecular interaction between LRRK2 and SV2A. SV2A, a synaptic vesicle protein, is the binding site of Levetiracetam (LEV), a compound widely used in human therapy for the treatment of epilepsy. Binding of LEV to SV2A reduces neuronal firing through modulation of vesicle trafficking, albeit by an unclear molecular mechanism. Interestingly, LEV significantly counteracts the effect of LRRK2 G2019S pathological mutant in three different experimental cell models. Our data strongly suggest that LEV treatment may have a neuroprotective effect on the toxicity of the LRRK2 pathological mutant. Our attention also focused on another actor involved in the regulation of vesicular trafficking: Sec8. Sec8 is a member of the exocyst complex, an evolutionarily conserved multisubunit protein complex mainly involved in the transport of secretory vesicles to the plasma membrane. Our experimental results indicate that LRRK2 interacts with Sec8 and that LRRK2 by its kinase activity regulates the exocyst subunit assembly. Moreover, the overexpression of Sec8 significantly corrects the pathological effect of the LRRK2 G2019S mutant. Our results strongly suggest an interesting molecular mechanism by which LRRK2 might modulate vesicle trafficking. Finally, all these results may have important implications for the definition of new therapeutic approaches/targets for PD treatment.