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Review
. 2021 Jan 21;22(3):1045.
doi: 10.3390/ijms22031045.

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

Vinita G Chittoor-Vinod  1 , R Jeremy Nichols  1 , Birgitt Schüle  1
Affiliations
Review

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

Vinita G Chittoor-Vinod et al. Int J Mol Sci. .

Abstract

Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson's disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer's pathology, hailing LRRK2 parkinsonism as the "Rosetta stone" of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors-either increasing toxicity or providing resilience-will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration.

Keywords: GWAS; LRRK2; Parkinson’s disease; environmental risk factors; genetics; modifier; neuropathology; parkinsonism; polygenic risk score.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Domain architecture, genetic risk variants, and regulatory phosphorylation sites of LRRK2 (leucine-rich repeat kinase 2). LRRK2 is a large kinase of 2527 amino acids with multiple identifiable functional domains. Variants classified as pathogenic according to MDSGene are in magenta, while risk factor variants pending conclusive classification are in orange; putative protective mutations are in blue; variants associated with inflammatory bowel disease (IBD) are in yellow. Regulatory phosphorylation sites are in green, and LRRK2 autophosphorylation site Ser1292 is in teal. ARM—armadillo domain; ANK—ankyrin domain; LRR—leucine-rich repeat domain; Roc—GTPase domain; COR—carboxy terminal of Roc domain.
Figure 2
Figure 2
Frequency of neuropathologic disorders with a clinical diagnosis of idiopathic Parkinson’s disease (PD) and LRRK2 parkinsonism. The pie charts show the frequency of pathologic disorders that present with clinical parkinsonism without dementia (n = 132), adapted from Dickson et al. (2018) [98], and LRRK2-PD from cases and case series described in the literature (n = 74; Table 1). Abbreviations: Lewy body disorder (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), vascular parkinsonism (VaP), and substantia nigra degeneration (SND). For details on neuropathological assessments, see Table 2.
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