LRRK2 a pivotal player in mitochondrial dynamics and lysosomal clustering: highlights to sporadic Parkinson's disease

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder affecting more than 1% of the population over 65 years of age. Dominant mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are found associated with both familial and sporadic cases and represent the most frequent genetic lesions associated with PD. Remarkably, lrrk2 mutations cause PD with age-related penetrance and clinical features similar to late-onset sporadic PD (sPD). LRRK2 is a complex and large protein constituted by multiple domains executing several functions, including GTP hydrolysis, kinase activity and protein binding. Although the cellular function of LRRK2 is largely unknown there is increasing evidence that LRRK2 posits a role in autophagic regulation, microtubule (MT) dynamics, and mitochondrial function. In our recent report, we tackled LRRK2 physiological role taking advantage of a potent and selective inhibitor (LRRK2-IN-1) of LRRK2 kinase activity. We evaluated LRRK2-IN-1 effects on several mechanisms known to be impaired in PD, such as MT network and trafficking, mitochondrial dynamics and function and the autophagic-lysosomal pathway. Importantly, we found that LRRK2 is necessary to maintain the levels of acetylated tubulin, which is a post-translational modification essential for MTs structure and function and with a prevalent role for axonal intracellular trafficking. In addition, we also provided evidence that LRRK2 kinase activity regulates mitochondrial dynamics through phosphorylation of mitochondrial dynamin-like protein (Drp1) increasing mitochondrial fission. Adding up, LRRK2 kinase activity is essential for regulation of lysosomal clustering and distribution through Rab7.  Therefore, our recent findings reveal novel insights into the function of LRRK2 in a normal or diseased context.