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.
Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis.
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.
One major advance in this field has been the discovery of several genes associated to familial PD, including alpha synuclein, parkin, LRRK2, etc., thereby providing important insight toward basic research approaches.
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.
Small GTPases are critical modulators of p38 activation and thus, their functional interaction with aSyn and LRRK2 could explain much of the detailed mechanics of autophagy in Parkinson´s disease.We propose a novel hypothesis for a more comprehensive working model where autophagy is controlled by upstream pathways, such as GTPase-p38, that have been so far underexplored in this context.
Leucine-rich repeat kinase 2 (LRRK2) is the genetic cause of both familial and idiopathic Parkinson's disease (PD), and it is associated with neuronal death, vesicle trafficking, mitochondrial dysfunction, and inflammation.
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.
Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD.