Wallings, R;
Manzoni, C;
Bandopadhyay, R;
(2015)
Cellular processes associated with LRRK2 function and dysfunction.
FEBS J
, 282
(15)
pp. 2806-2826.
10.1111/febs.13305.
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Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) encoding gene are the most common cause of monogenic Parkinson's Disease (PD). The identification of LRRK2 polymorphisms associated with increased risk for sporadic PD, as well as the observation that LRRK2-PD has an almost indistinguishable pathological phenotype from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic PD cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with PD reside within the enzymatic core of LRRK2, suggesting the modification of its activity greatly impacts disease onset and progression. Although progress has been gained since its discovery in 2004, there is still much to be understood regarding LRRK2's physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review will discuss the state of current knowledge for the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. As well, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function shall also be discussed. This article is protected by copyright. All rights reserved.
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