Function and Pathogenic Mechanism of LRRK2 in Parkinson's Disease

National Institute On Aging

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Abstract

Background: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinsons disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to the PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. Methods: We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2/) and control (Lrrk2+/+) mice at 2 and 12 months of age. We examined the SPN nuclear DNA damage and epigenetic modifications; the SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of the Lrrk2+/+ and Lrrk2/ mice from 2 to 24 months of age. In an attempt to recapitulate the in vivo findings in cell cultures as a more amendable system for the future mechanistic studies, we also performed preliminary studies on the primary cultured SPNs derived from the Lrrk2+/+ and Lrrk2/ mice as well as the PD-related G2019S and R1441C mutant mice. Results: Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in the SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in the aged Lrrk2/ striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and -Aminobutyric acid type A (GABAA) receptor inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2/ and R1441C SPNs. Conclusions: Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that the PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.