Neuroinflammatory and Motor Alterations in LRRK2*G2019S Transgenic Mice Without Enhanced Vulnerability to Aging or Chronic MPTP‐Induced Nigrostriatal Neurodegeneration

Abstract

LRRK2 G2019S mutation is the most common genetic cause of Parkinson's disease (PD) producing clinical manifestations similar to sporadic PD patients, hinting at the relevance of this mutation in the pathophysiological mechanisms of the disease. However, its role potentiating nigrostriatal neurodegeneration, particularly in response to mitochondrial dysfunction, remains unclear. Here, using histological, neurochemical and behavioral analyzes, we provide a complete characterization of a mouse model expressing the human LRRK2 G2019S mutation (hLRRK2*G2019S mice), in the context of aging and toxin‐induced parkinsonism. hLRRK2*G2019S young adult mice showed significant microglial activation and deficits in motor coordination, whereas aged transgenic displayed a hyperactive phenotype, despite the absence of evidence for nigrostriatal neurodegeneration in either young adult or aged animals. Furthermore, we assessed the vulnerability of LRRK2*G2019S transgenic mice to the chronic exposure to the mitochondrial complex I inhibitor 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Notably, no exacerbation of nigrostriatal neurodegeneration was observed in hLRRK2*G2019S mice, suggesting that this mutation does not increase sensitivity to mitochondrial stress. However, hLRRK2*G2019S MPTP‐treated mice present alterations, relative to WT counterparts, in the glial response induced by the neurotoxic treatment. These findings suggest that the G2019S mutation modulates the neuroimmune response but does not exacerbate nigrostriatal neurodegeneration in response to mitochondrial dysfunction. This highlights the mutation's complex role in PD pathophysiology.