Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background.
Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (<i>LRRK2</i>) gene are the most common genetic predisposition to develop Parkinson's disease (PD).
Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627.
G2019SLRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria.
The further study and understanding of the route by which alpha-synuclein and LRRK2 lead to PD, and how these processes can be therapeutically manipulated, is likely to lead to new disease-modifying treatments.
We further found that PD mutation R1441C/G in the GTPase domain causes reduced GTP hydrolysis activity, consistent with the altered enzymatic activity in the mutant LRRK2 carrying PD familial mutations.
Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2PD-risk variant were evaluated for association with DLB.
We conclude that in these patients carrying the LRRK2Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD.
Current guidelines recommend testing for LRRK2 variants in familial PD or in specific populations (ancestry), and for the recessive genes in early-onset PD.
Among women who were non-carriers of GBA and LRRK2G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001).
The frequency of LRRK2Gly2385Arg mutation in Hong Kong Chinese with early-onset (age < or =45 years) Parkinson's disease was identified and compared with late-onset patients (age >50 years) and controls.
Additionally, the model could predict the conversion of scan without evidence of dopaminergic deficit to Parkinson's disease, as well as discriminate between normal and impaired subjects with leucine-rich repeat kinase 2 mutations.
Recently, a mutation in the LRRK2 gene, G2019S, was associated with 3-41% and 1-2% of familial and sporadic PD, respectively suggesting a pivotal role of LRRK2 in PD.