Human genetics studies have linked LRRK2 as a major genetic contributor to familial and sporadic Parkinson's disease (PD), a neurodegenerative movement disorder that inflicts millions worldwide.
The "common" LRRK2G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease.
In this review, we focus on the recent advances on the role of Rab GTPases in the biology of two main proteins involved in Parkinson's disease: LRRK2 and α-synuclein, given that mutations in their genes (LRRK2 and SNCA) cause familial and sporadic Parkinson's disease.
Therefore, we investigated their role in eye movement preparation in sporadic Parkinson's disease and in a very infrequent variant affecting the Parkin gene.
Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.
These findings show that the cerebral cortex in familial PD linked with G2019SLRRK2 is affected in a similar way than that seen in sporadic PD without cognitive impairment.
Similar results were obtained when the cells were treated with a proteasome inhibitor, MG132.Furthermore, in a case control study involving 753 subjects, we demonstrated that the parkin promoter -258G variant was associated with an increased risk of sporadic Parkinson's disease (PD) in the elderly ethnic Chinese population.
However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear.
Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease.
Together, these findings suggest that downregulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD, while overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in PD.
Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.
As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies.
In summary, our footprint-free LRRK2-G2019S isogenic cell lines allow standardized, genetic background independent, in vitro PD modeling and provide new insights into the role of LRRK2-G2019S and S129P-αS in the pathogenesis of PD.
Recent research has focused on neuroinvasive influenza A viruses (IAV), whereas a genetic link between sPD and tuberculosis has arisen in LRRK2 - dependent maturation of the phagosome.
Our study indicates that this LRRK2 p.2385G>R substitution contributes to the development of PD in ethnic Han-Chinese population, which may play important implications for future study on molecular genetics and pathogenesis of PD.