LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's disease
Ruey–Meei Wu
2019
Neurological Therapeutics
Parkinson's disease is a complex neurodegenerative disease, caused by a combination of various genetic and environmental factors. Mutations in LRRK2 are found in a significant proportion of patients with sporadic and familial Parkinson's disease (PD). The LRRK2 protein contains multi-domains including a GTPase and kinase domains playing important functions in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. Although the mechanisms
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... d the pathogenesis of LRRK2 mutations are still uncertain, recent studies in the brains of PD patients and in animal models of parkinsonism indicate the emerging role of autophagy in the pathogenesis of PD. By using the transgenic mouse model overexpressing human LRRK2 gene, R1441G heterozygous (R1441G HET), or homozygous (R1441G HOM) mutation in the human LRRK2 gene, we tested the hypothesis of autophagy in association with the pathophysiology of LRRK2 mutation. We performed comprehensive behavior tests of motor function in these mice up to 12 months, investigate the GTPase activity, observed the histological and electro-microscopic image findings of the substantia nigra, and measure the protein expression of mitochondria and autophagy in the brain. Our results showed that there were body weight loss and impaired exploratory rearing behavior in both of hLRRK2 R1441G HET and HOM mice at 9 and 12 months old. Moreover, the hLRRK2 R1441G HOM mice had abnormal gait pattern mimicking the gait disturbance seen in patients with PD, in terms of decrease in swing speed, stride length and front paws of base of support, and increase in stand, step and duty cycles, and hind paws of base of support. On the molecular functional study, hLRRK2R1441G HOM demonstrated increase in GTPase activity and decrease in autophagy-related makers and mitochondria dynamic proteins by western blot at age 12 months old. As expected, abnormal accumulation of lysosome and mitochondria morphology were observed in the substantia nigra of hLRRK2 R1441G HOM brain by transmission electron microscopy at 12 months old of the mice. Our study provides evidence for the discovery of new drugs targeting the autophagy dysfunction in patient with PD and ROCO domain variants.
doi:10.15082/jsnt.36.6_s101
fatcat:v4dl5btkjzhxhmgpy2dz6kvqvu