LRRK2 mutations: at the crossroads of dopamine, iron, and calcium imbalance in Parkinson's disease.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. The G2019S mutation in the leucine‑rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of familial and sporadic PD. In dopaminergic neurons, increased kinase activity caused by LRRK2‑G2019S mutation impairs synaptic vesicle recycling and dopamine storage, increasing cytosolic dopamine, which is prone to oxidation and generates reactive oxygen species. Simultaneously, the mutation alters iron metabolism through Rab misregulation, increasing iron uptake and lysosomal dysfunction, further amplifying oxidative stress and creating a pro‑ferroptotic environment. At the same time, dysregulated calcium signaling, driven by the enhanced activity of L‑type calcium channels and impaired mitochondrial calcium buffering via the mitochondrial calcium uniporter, enhances mitochondrial dysfunction. This minireview integrates current evidence linking LRRK2‑G2019S to these pathological pathways, highlighting this mutation's role in dopamine, iron, and calcium imbalance. Understanding this molecular interplay may provide novel insights into PD pathogenesis and guide the development of targeted neuroprotective therapies.