The effects of LRRK2 mutations on age associated Parkinson’s disease pathology including dopamine receptor signaling and mitochondrial function

Abstract

The incidence of neurodegenerative diseases, such as Parkinson’s disease (PD) is increasing as the population ages that is one of the highest risk factors that induces PD. PD is characterized by progressive neurodegeneration of dopaminergic neuron in the substantia nigra pars compacta (SNpc). Genetic factors are also high risk factors of PD. Leucine-rich repeat kinase 2 (LRRK2) is one of the most prevalent genetic factors that induces PD. LRRK2 G2019S and R1441G are well known and frequent genetic mutations in human patients. Recent studies have suggested that an LRRK2 mutation could be involved in mitochondrial dysfunction. In this study, I researched about the effects of LRRK2 and G2019S mutations on mitochondrial dynamics relative to age. LRRK2 G2019S mice showed decreased motor activities not only aging but also G2019S mutation in rotarod test. Mitochondrial fusion-fission related gene expression changes were determined in the LRRK2 G2019S PD models. Dopamine receptor agonists are commonly used for PD drugs. Previously, it has been suggested that the D3 receptor (D3R) is related to cognitive function. It has been known that administration of (±) -7-Hydroxy-2- (di-n-propylamino) tetralin hydrobromide (7-OH-DPAT) into MPTP-PD model mice improved the motor behavior. Thus, I determined the effect of the 7-OH-DPAT in LRRK2 R1441G mice. Administration of 7-OH-DPAT attenuated the motor deficits, increased the number of neuronal cells, and decreased anxiety-like behavior in LRRK2 R1441G mice. Interestingly, the administration of 7-OH-DPAT increased the BDNF levels in the striatum (ST) region. Taken together, I determined the age dependent phenotypes of LRRK2 G2019S and R1441G transgenic mice. I also found the changes of mitochondria-related genes in LRRK2 G2019S PD models. These results elucidate the LRRK2 function in the mitochondria gene expression. My results suggest that mitochondrial dynamics can be applied for future therapeutic approach of PD. Also, in my results, administration of D3R agonists have shown improvements in motor performances as well as improvements of cognitive function. The number of neuronal cells in various brain regions also increased. My results suggest that D3R agonists could be used for PD treatment and promising future therapeutic targets.