Understanding molecular mechanisms underlying leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease

Abstract

Parkinson’s disease is a common neurodegenerative movement disorder. Mutation of LRRK2 is pathogenic in PD. More than 20 mutations of LRRK2 have been reported in Parkinson patients. Most importantly, 5–6% of familial PD patients harbor these mutations. Some of the mutations were shown to be able to increase LRRK2 kinase activity. Over-expression of LRRK2 in transgenic mice leads to tauopathy and hyperphosphorylated tau, indicating the pivotal role of LRRK2 in PD pathogenesis. We aim to elucidate the importance of LRRK2 in the pathogenesis of PD by studying the effects of this protein on neuronal cell death under oxidative stress. MATERIALS AND METHODS: We have generated LRRK2 knockin (KI) mice bearing the pathogenic point mutation R1441G of LRRK2 by inserting a targeting vector via homologous recombination into the murine LRRK2 locus. We compared the LRRK2 expression level, mitochondria number and movement ability in the KI mouse and control mouse lines. We characterized the LRRK2 R1441G KI mice and control mice by immunohistochemistry of tyrosine hydroxylase (TH) to identify TH+ neurons and measured mice behave after challenged with MPTP injection (IP) to induce nigrostriatal degeneration. RESULTS: Our preliminary data showed that LRRK2 R1441G induced a less degree of sensitivity to oxidative stress compared with that exhibited by the control mice induced by MPTP. The dopamine transporter should be affected or Impaired in this KI mice. The results of this study have important implication on understanding the LRRK2 funciton in the pathogenesis of PD.