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Review
. 2022 Mar;45(3):224-236.
doi: 10.1016/j.tins.2021.12.002. Epub 2022 Jan 4.

LRRK2 and idiopathic Parkinson's disease

Emily M Rocha  1 , Matthew T Keeney  2 , Roberto Di Maio  1 , Briana R De Miranda  3 , J Timothy Greenamyre  4
Affiliations
Review

LRRK2 and idiopathic Parkinson's disease

Emily M Rocha et al. Trends Neurosci. 2022 Mar.

Abstract

The etiology of idiopathic Parkinson's disease (iPD) is multifactorial, and both genetics and environmental exposures are risk factors. While mutations in leucine-rich repeat kinase-2 (LRRK2) that are associated with increased kinase activity are the most common cause of autosomal dominant PD, the role of LRRK2 in iPD, independent of mutations, remains uncertain. In this review, we discuss how the architecture of LRRK2 influences kinase activation and how enhanced LRRK2 substrate phosphorylation might contribute to pathogenesis. We describe how oxidative stress and endolysosomal dysfunction, both of which occur in iPD, can activate non-mutated LRRK2 to a similar degree as pathogenic mutations. Similarly, environmental toxicants that are linked epidemiologically to iPD risk can also activate LRRK2. In aggregate, current evidence suggests an important role for LRRK2 in iPD.

Keywords: autophagy–lysosomal pathway; endogenous protein expression; environmental toxicants; kinase; oxidative stress.

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Conflict of interest statement

Declaration of interests None declared by authors.

Figures

Figure 1.
Figure 1.. Architecture of the LRRK2 protein and effects of Parkinson’s disease-associated mutations.
LRRK2 consists of 2527 amino acids and has 7 distinct domains: ARM, armadillo; ANK, ankyrin; LRR, leucine-rich repeat; ROC, Ras of complex; COR C-terminal of ROC; Kinase; and WD40, WD40 domain. LRRK2’s enzymatic domains are a ROC-COR GTPase domain and a serine/threonine kinase domain. The most common pathogenic mutations (in red) arise in the ROC-COR GTPase or kinase domain of the protein. The proposed mechanism of how each mutation affects the dynamics of LRRK2 is described below each mutation. Also depicted are the autophosphorylation sites, pSer1292 (green) and pThr1503 (purple). The autophosphorylation site pSer1292 is the most widely studied and is commonly used as a readout of kinase activity. The Thr1503 autophosphorylation site has been used in several studies as an indicator of kinase activity, however, this site has yet to be validated in an endogenous system. Phosphorylation sites in the N-terminal (pSer910 and pSer935) mediate 14–3-3 binding to LRRK2.
Figure 2.
Figure 2.. The role of LRRK2 in endolysosomal trafficking.
In PD, elevated LRRK2 activity can lead to accumulation of Rab5-positive early endosomes as well as impairment in the ESCRT machinery. These deficits can in turn prevent early to late endosomal maturation; as a result, there are fewer Rab7-positive late endosomes. These deficits in vesicle trafficking can, in turn, cause an increase in LRRK2 activity, albeit through an undefined mechanism(s). Impaired late endosomal–lysosomal fusion caused by aberrant LRRK2 kinase activity can result in stressed lysosomes, which then recruit and activate LRRK2, possibly via Rab29. At a stressed lysosome, active LRRK2 can recruit and phosphorylate Rab8A and Rab10. The biological significance of lysosomal recruitment of Rab10 and Rab8A has yet to be fully characterized but likely involves lysosomal vesicle formation / budding and exocytosis. At the recycling endosome, LRRK2 can be activated by the retromer complex. Although the mechanism responsible for this recruitment is currently unknown, it is clear that LRRK2 recruitment to the recycling endosome can result in improper retrograde trafficking from the recycling endosome to the trans-Golgi network (TGN). Moreover, at the TGN, high levels of Rab29 (in overexpression systems) can recruit and activate LRRK2, which results in accumulation of Rab10 positive vesicles at the TGN, which in turn, can lead to impaired anterograde trafficking.
Figure 3, Key Figure:
Figure 3, Key Figure:. Activation of wildtype LRRK2 kinase.
Environmental contaminants linked to PD [82] and PD-associated risk genes [2] affect mitochondrial function and the endolysosomal system, either directly or indirectly. Interestingly, mitochondrial dysfunction and endolysosomal stress are key mediators of LRRK2 kinase activation. A convergent event of both mitochondrial and lysosomal dysfunction is the generation and accumulation of ROS, which in turn can activate LRRK2. Whether the ROS buildup from damaged lysosomes is released directly from these lysosomes or is a downstream consequence is currently undefined. Enhanced LRRK2 kinase activity, as a result of either mitochondrial dysfunction or stressed lysosomes, can further damage lysosomes and result in membrane permeabilization and leakage of damaged cargo and proteins, including α-synuclein into the cytoplasm. This, in turn, results in the toxic accumulation and aggregation of α-synuclein. The phosphatase PPM1H, which is known to counteract LRRK2 activity by dephosphorylating specific Rab proteins (e.g. Rab8A, Rab10) may normalize aberrant LRRK2 kinase activity. However, this signaling axis remains to be explored.
Figure I (for Box 1).
Figure I (for Box 1).
Schematic diagram of endolysosomal pathways. (1) From plasma membrane endocytosis to the formation of early endosomes. This is subsequently followed by two divergent pathways: (2) formation of recycling endosomes and (3) maturation to late endosome and eventual (4) lysosomes. (5) The retromer complex can traffic cargo to the TGN and (6) support anterograde vesicular trafficking from the TGN.
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References

    1. Ball N, et al. (2019) Parkinson’s Disease and the Environment. Front Neurol 10, 218. - PMC - PubMed
    1. Blauwendraat C, et al. (2020) The genetic architecture of Parkinson’s disease. Lancet Neurol 19, 170–178 - PMC - PubMed
    1. Leonard H, et al. (2020) Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease. J Med Genet 57, 331–338 - PMC - PubMed
    1. Reeve A, et al. (2014) Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev 14, 19–30 - PMC - PubMed
    1. Artzi M, et al. (2017) DaT-SPECT assessment depicts dopamine depletion among asymptomatic G2019S LRRK2 mutation carriers. PLoS One 12, e0175424. - PMC - PubMed

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