Does motor cortex plasticity depend on the type of mutation in the leucine‐rich repeat kinase 2 gene?

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) account for up to 13% of dominant familial Parkinson’s disease (PD) cases and 1% to 2% of sporadic PD patients. The clinical and pathological features of LRRK2-PD are often indistinguishable from idiopathic PD (iPD). The LRRK2 protein belongs to the tyrosine-kinases family and contains several domains including a RAS/Guanosine-50triphosphate (GTP)ase-like (Roc) and a kinase domain. In these 2 domains, the G2019S (kinase subunit) and the R1441C (Roc domain) are the most frequent diseasesegregating mutations. Importantly, in southern Italy, the R1441C mutation is more frequent than the G2019S mutation. Recent evidence pointed out that LRRK2 acts directly at the secretory and endocytic molecular machinery. Indeed, a proper vesicular trafficking and spatial distribution in the presynaptic pool depend on LRRK2 because it has an integral part of the presynaptic protein complex. Based on the LRRK2 role on synaptic transmission, Ponzo and colleagues recently reported that G2019S LRRK2-PD patients have abnormal long-term potentiation-like (LTP) plasticity following intermittent theta-burst stimulation over the primary motor cortex. Similarly, such patients displayed a striking reduction of short-intracortical inhibition (SICI), suggesting a possible impairment of Gamma-aminobutyricacid (GABA)ergic neurotransmission as determinant of cortical hyperexcitability. We investigated motor cortex excitability and plasticity on the more affected side in 8 LRRK2-PD patients (6 men, mean age 61.9 6 3.9 years, average disease duration 8.4 6 2.1 years, mean ON UPDRS-III 23.4 6 4.7, L-dopaequivalent dose 1015.9 6 231.2 mg) harboring the R1441C mutation, 11 iPD patients (8 men, mean age 62.3 6 2.2 years, average disease duration 8.6 6 1.2 years, mean ON UPDRS-III 19.2 6 3.9, L-dopa-equivalent dose 838.1 6 117.1 mg) and 10 healthy subjects (HS; 8 men, mean age 59.4 6 1.6 years). Motor cortex excitability profile evaluated by means of motor thresholds, SICI, intracortical facilitation, short-latency afferent inhibition did not exhibit any difference among the 3 groups (Pmin 5 .442). Conversely, we observed the lack of LTP-like motor cortex plasticity in R1441C-LRRK2 patients when compared with HS and with a similar profile observed for iPD patients (mixed model analysis of variance: significant time [F2,46 5 4.241, P 5 .02], group [F2,23 5 9.336, P 5 .001], and time by group [F4,46 5 4.345, P 5 .005] interaction; Fig. 1). Our results, together with those of Ponzo and colleagues, suggest that G2019S and R1441C mutations might impact differently on motor cortex excitability and plasticity. The first mutation causes disinhibition and hyperexcitability of the motor cortex, and the second one the disruption of motor cortex LTP-like plasticity. Interestingly, it has been recently demonstrated that both mutations seem to regulate synaptogenesis and function in the striatum by modulating a protein kinase activity. The G2019S-LRRK2 mutation increases protein kinase activity and induces hyperexcitability of the corticostriatal circuit, whereas the R1441C-LRRK2 mutation might be a negative modulator of protein kinase regulatory subunit II b that is important for the induction of LTP, causing an overall impairment of synaptic transmission as a result of the delay of spine maturation. Certainly more studies will be needed to fully understand the role of these mutations in the pathogenesis of familial and iPD conditions.