Cellular processes associated with LRRK2 function and dysfunction

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.

Keywords: GTPase; LRRK2; LRRK2 kinase inhibiton; autophagy; cytoskeleton; genetics; kinase; retromer complex; signalling mechanisms; vesicle trafficking.

Figure 1

LRRK2 domian structure, pathogenic mutations, constitutive and autophosphorylation sites important for understanding LRRK2 function and dysfunction. Pathogenic mutations and susceptibility polymorphisms are shown in red, constitutive phosphorylation in green and a selection of autophosphorylation sites shown in black. The blue curved arrows depicts intramolecular regulation of kinase activity by other LRRK2 domians; IkappaB and casein kinase 1 alpha (shown in yellow) phosphorylate and PP1 alpha dephosphorylates (shown in fawn) LRRK2 at S910/S935 sites.

Figure 2

Implication of LRRK2 in signalling pathways. The cartoon depicts multiple signalling pathways that have been associated with LRRK2 function in physiology and/or disease. Signalling pathways are sometimes interconnected and they coordinate the control over multiple cellular activities as reported in the red boxes.

Figure 3

Implication of LRRK2 in immune‐specific functions. The cartoon summarizes the LRRK2‐specific events that have been described to occur in cells from the immune system.

Figure 4

Implication of LRRK2 in cellular functions. The cartoon represents the cellular processes (red boxes) that have been associated with LRRK2 function in physiology and/or disease. The data are from a multitude of experiments run by laboratories across the world over the past decade and are based on different model systems and experimental approaches. It is not possible to describe a hierarchy among these processes, or score them based on reliability. More investigations are needed to determine which of these processes are directly controlled by LRRK2 and which appear to be LRRK2 regulated or whether they are just consequences of other LRRK2 primary functions. It remains to be determined if all of these functions co‐occur in a single cell type or whether LRRK2 orchestrate different, specific functions in different cell types.