Parkinson?s disease (PD) is the second most common neurodegenerative disease of aging. Mutations in LRRK2 are associated with both inherited and sporadic forms of PD. LRRK2 is highly enriched in spiny projection neurons (SPN) in the dorsal striatum. However, the physiological role of LRRK2 in SPNs remains elusive. Our previous observations suggest a linkage between the pathogenic R1441C mutation and aberrant PKA signaling in SPNs. However, the analyses were limited by the inherent resolution provided by conventional biochemical approaches and microscopy. Here, we seek to provide more precise information about the pathophysiological consequences of LRRK2 mutations in SPNs. In particular, it is our central hypothesis that LRRK2R1441C mutation leads to aberrant dopaminergic signaling in SPNs. The resultant striatal dysfunction, in turn, contributes to the symptomatology of PD. Given that among the most significant changes that occur during the disease progress is the imbalance of corticostriatal plasticity, we will examine if LRRK2 mutations alter corticostriatal plasticity, through PKA and dopamine signaling dysregulation. These data will be integrated with our findings on striatal- dependent motor learning in a whole-animal setting in order to establish that the motor learning impairment is a phenotypic outcome of dopamine-dependent LRRK2?s role on plasticity. In conjunction with standard cellular, molecular, and electrophysiological approaches, our investigations will capitalize on a combination of cutting- edge approaches that overcome obstacles that have impeded progress to date. These include, knock-in LRRK2 mutant mice, striatal pathway-specific reporter mice, and viral gene delivery. The successful achievement of these studies will significantly advance our understanding of the molecular mechanisms underlying corticostriatal plasticity in PD, and in doing so, will promote the development of new therapies for PD patients in the future.
The proposed research aims to determine the alterations of corticostriatal plasticity of indirect striatal projection neurons harboring pathogenic LRRK2 mutations. The knowledge gained will provide a framework for novel therapeutic strategies.
|Tayebi, Nahid; Parisiadou, Loukia; Berhe, Bahafta et al. (2017) Glucocerebrosidase haploinsufficiency in A53T ?-synuclein mice impacts disease onset and course. Mol Genet Metab 122:198-208|