LRRK2 mutations and neurotoxicant susceptibility

Abstract

Interactions between genetic and environmental factors are thought to contribute to the pathogenesis of the majority of Parkinson's disease (PD) cases. However, our understanding of these interactions is at an early stage. Mutations in leucinerich repeat kinase 2 (LRRK2) are the most common cause of hereditary PD. Penetrance of LRRK2 mutations is incomplete and variable, suggesting that other environmental or genetic factors may contribute to the development of the disorder. Recently, using animal models, several attempts have been made to understand if LRRK2 may mediate sensitivity to environmental neurotoxicants. Here, we critically review the most current data on how LRRK2 mutations influence neurotoxicity in PD models.

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

“…LRRK2 mutations are the most common genetic cause of PD, with the most common mutations being a glycine to serine substitution (G2019S) in LRRK2's kinase domain which increases kinase activity [61] . Autosomal dominant mutations can lead to lateonset PD, with polymorphisms in LRRK2 also being a risk factor for sporadic PD [62] .…”

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

“…Outside of traditional transgenic mice, the acute induction of α‐syn overexpression via viral vector or injection of preformed α‐syn fibrils also suggests a role for LRRK2 in α‐syn neurotoxicity. BAC‐mediated expression of G2019S‐LRRK2 in rats causes a very mild motor impairment with no dopaminergic cell loss even at 12 months of age (Lee & Cannon, ; Walker et al., ). However, injection of an AAV coding for α‐syn (Daher et al., ) in the SNc of these G2019S‐LRRK2 rats induces a loss of TH‐positive neurons that appears slightly more pronounced as compared to that seen in WT‐LRRK2 rats.…”

Rodent Model of Parkinson’s Disease: Unilateral or Bilateral?

“…LRRK2 is expressed in subcellular part of neurons [54]. Mutation of LRRK2 is prevalent to the inherited PD [55]. The pathogenesis is probably owing to aberrant kinase activity, the abnormal phosphorylation of substrates, and misregulation of binding partners and regulators [56].…”