Effects of LRRK2 genetic mutations on mitochondrial function in Parkinson's disease model mice

Abstract

Parkinson’s disease (PD) is progressive and complex neurodegenerative brain disorder that results in degeneration of nigrostriatal dopaminergic neurons. PD is caused by a number of factors, including genetic mutations, oxidative stress, mitochondrial abnormalities, and aging, etc. Mutation of leucine-rich repeat kinase 2 (LRRK2) which contain GTPase and kinase domain is one of the most popular genetic cause of PD. To identify the progressive changes of mitochondrial dynamics by aging in LRRK2 G2019S and LRRK2 R1441G mutation, we used LRRK2 G2019S and LRRK2 R1441G mice which showed significantly worse performance in rotatod test at over 11 month of age. We determined that mitochondria complex Ⅱ/Ⅲ activity were decreased by mutation in group of LRRK2 R1441G mice at the 8 and 20 months of age. The cellular ATP levels were decreased at the 1 month of age in the striatum of LRRK2 R1441G mice. We determined the expression level of Mitochondria fission 2(MFN2), mitochondria fission-fusion related genes, was decreased in the striatum of LRRK2 G2019S mice by mutation. The mRNA expression level of MFN1 is decreased in R1441G mice over 8 months of age by aging. Our results suggest that the LRRK2 G2019S and R1441G mutation and aging affect to the mitochondrial dynamics. Mitochondrial dynamics can be applied for future therapeutics for PD.