Abstract
Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made 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 discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.
Highlights
Parkinson’s disease (PD) is an insidious and progressive neurodegenerative disease, affecting around 1–2% of the population over the age of 65 [1]
leucine-rich repeat kinase 2 (LRRK2) was described as a negative regulator of nuclear factor of activated T cells (NFAT), a protein involved in transcriptional regulation in T cells, macrophages, dendritic cells and neutrophils [162]; reinforcing the hypothesis that LRRK2 may have a precise role in the immune system because of the peculiar interaction partners through which it can exert tissue-specific functions
It is evident that there is still much to be understood about the LRRK2 protein regarding both its physiological and neurotoxic properties
Summary
Parkinson’s disease (PD) is an insidious and progressive neurodegenerative disease, affecting around 1–2% of the population over the age of 65 [1]. In the effort to tackle PD, there is a compelling need for a profound understanding of LRRK2 functions, as well as a description of the signalling pathways in which LRRK2 may be involved in diverse cell types, the identification of regulators of LRRK2 activity, binding partners and phosphorylation targets.
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