Objective: To evaluate the function role of ROC domain in the brains of LRRK2 transgenic mice model and normal control mice.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson’s disease (PD). LRRK2 gene encodes a large protein belongs to the family of ROCO proteins. LRRK2 mutations exhibit a clinical and pathological phenotype indistinguishable from idiopathic PD. Recent documents have shown the pathologic mutants of LRRK2 could reduce the rate of GTP hydrolysis and increase the kinase activity and GTP-binding activity and then cause cell death in vitro and in vivo. Notably, the process of cell death may be involved in several signalling pathway containing the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction.

Methods: Mice overexpressing the mutated form of hLRRK2 (R1441G) and their age-matched controls were cardiac perfused and fixed for examination of mitochondria and lysosome morphology in dorsal striatum using electron microscopy. Protein-protein interaction was determined by immunoprecipitation and Western blotting. The GTPase activity was determined using an ATPase/GTPase ELIPA Biochem Kit.

Results: We shown the neurite degeneration was also investigated in substantia nigra of transgenic LRRK2 R144G homozygous mice. In addition, we found the enhancement of GTPase activity in the brain of LRRK2 R144G homozygous mice. Drp1 was increased in the mitochondrial fraction of transgenic LRRK2 R144G homozygous mice brain. Levels of proteins related to mitochondrial fusion, including Mfn1, Mfn2, and Opa1, were not altered. Furthermore, p62 and LC3II were also increased in brain tissue.

Conclusions: Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and mitophage in brain. Thus, disruption of mitochondrial dynamics and mitophage may underlie the pathogenesis of LRRK2 R1441G mutation in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-genetics-and-functional-studies-of-lrrk2-gene-variations-in-parkinsons-disease/