Abstract
LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson’s disease (PD). Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however, studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in Caenorhabditis elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the mitogen activated protein kinase (MAPK) pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GTPase-activating proteins and GTPase exchange factors are another strong theme in LRRK2 biology, with LRRK2 binding to rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1, and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term PD.
Highlights
Parkinson’s disease (PD) is the most common age-related motor disorder (Hsu et al, 2010a; Ferree et al, 2012)
Multiple studies have focused on its kinase activity, with the resulting identification of LRRK2 inhibitors that might have therapeutic benefit
The function of LRRK2 kinase activity remains unclear, with LRRK2 itself being the most robust substrate identified to date
Summary
Parkinson’s disease (PD) is the most common age-related motor disorder (Hsu et al, 2010a; Ferree et al, 2012). Current studies with a new nematode model in our laboratory shows that both WT and G2019S LRRK2 potentiate age-related loss of dopaminergic neurons (and of their processes), suggesting that understanding the interaction between LRRK2 and α-synuclein is important for modeling the pathophysiology of PD.
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