Inhibition of PKA in the striatum as a mechanism to reverse LRRK2 mutant-induced phenotype

The cell selective degeneration and/or death of the midbrain dopaminergic neurons is considered a pathological hallmark of Parkinson’s disease (PD). The resulting impairment of dopaminergic innervation of the cells in the striatum is the underlying neurological basis of PD-related movement disorders, triggers functional, and morphological alterations of the striatal projection neurons (SPNs). This is also accompanied by a loss of the spines and glutamatergic synapses in animal / murine models of PD as well as seen in the postmortem brains of patients (Gerfen and Surmeier, 2011; Stephens et al., 2005), (Zaja-Milatovic et al., 2005). LRRK2 is particularly enriched in the striosomes of SPNs as opposed to its low expression in the midbrain dopaminergic neurons (Mandemakers et al., 2012). This distinct expression pattern in the brain indicates that LRRK2 might have a role, at least in some part, in how SPNs respond to dopamine stimulation normally and under pathological conditions.