Protective or Pathogenic? Kinase activity and the neurodevelopmental origins of G2019S LRRK2-Associated Parkinson's...

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common monogenic cause of Parkinson's disease (PD), with the p.Gly2019Ser (G2019S) variant being particularly prevalent. The LRRK2 gene encodes a large, multi-domain protein (LRRK2) belonging to the Roco family, possessing both kinase and GTPase activities. Because normal LRRK2 function is critical for neuronal development, synaptic plasticity, vesicle trafficking, mitochondrial homeostasis, and neuroinflammatory pathways, pathogenic LRRK2 variants likely impair these functions. This is supported by rodent models and induced pluripotent stem cell (iPSC) studies suggesting that G2019S LRRK2 variants accelerate neuronal differentiation and disrupt synaptic function early in development, while kinase overactivity (phosphorylation of various substrates) is critical during normal embryonic growth. Contrary to the dominant gain-of-toxic-function hypothesis, these observations support an alternative loss-of-function framework, whereby increased kinase activity may be a compensatory cellular strategy to counteract the loss or alteration of the homeostatic and neurodevelopmental functions associated with G2019S LRRK2. If validated by further studies, including ongoing LRRK2 kinase inhibitor trials, future LRRK2-PD therapeutic strategies may shift from broad kinase inhibition toward individualized modulation of specific LRRK2-mediated impairments, such as vesicle trafficking, mitochondrial integrity, or microglial dysfunction. Such an approach would recognize LRRK2-PD not as a single entity but as a biologically heterogeneous group of PD subtypes.