Immune function of LRRK2: focus on mitochondrial metabolism

Parkinson’s disease (PD) is the most common movement disorder affecting the elderly. The disease results from the death of neurons in the brain that secret dopamine leading to impaired movement. Although PD symptoms have been described for decades, no cure exists to prevent or stop the disease. Over the last two decades, several genes have been linked to PD. Among them, mutations in leucine-rich-repeat kinase 2 (LRRK2) stand as the most common genetic cause. LRRK2 is a large multidomain protein with a double enzymatic function (kinase and GTPase). LRRK2 kinase activity is increased in PD patients. Although PD is considered as a brain disease, recent evidence showed that the immune system plays an important role in the development of PD. LRRK2 is highly expressed in immune cells and both the LRRK2 level and kinase activity are upregulated in PD patients’ immune cells. In addition, recent studies showed that mutations in LRRK2 resulted in defects in the function of mitochondria, the powerhouse of the cell. Yet, the exact mechanism by which LRRK2 regulates mitochondrial function in immune cells is unclear.
In this thesis, we investigated LRRK2 regulation of mitochondrial function and energy production in immune cells. We proved that LRRK2 has a conserved role in mitochondrial energy generation. Mitochondrial defects could impair energy production resulting in cell death. Furthermore, we presented a better understanding of the influence of LRRK2 on stimulated immune cells. Additionally, we identified a novel protective effect of LRRK2 and its kinase function against the unique iron-dependent form of programmed cell death, ferroptosis, involved in PD development. Together these findings mean that LRRK2 contributes to the inflammatory process that may lead to the death of dopamine-secreting neurons.