Abstract
Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials. Although the precise pathophysiological functions of LRRK2 remain largely unknown, PD-associated mutants have been shown to alter various intracellular vesicular trafficking pathways, especially those related to endolysosomal protein degradation events. In addition, biochemical studies have identified a subset of Rab proteins, small GTPases required for all vesicular trafficking steps, as substrate proteins for the LRRK2 kinase activity in vitro and in vivo. Therefore, it is crucial to evaluate the impact of such phosphorylation on neurodegenerative mechanisms underlying LRRK2-related PD, especially with respect to deregulated Rab-mediated endolysosomal membrane trafficking and protein degradation events. Surprisingly, a significant proportion of PD patients due to LRRK2 mutations display neuronal cell loss in the substantia nigra pars compacta in the absence of any apparent α-synuclein-containing Lewy body neuropathology. These findings suggest that endolysosomal alterations mediated by pathogenic LRRK2 per se are not sufficient to cause α-synuclein aggregation. Here, we will review current knowledge about the link between pathogenic LRRK2, Rab protein phosphorylation and endolysosomal trafficking alterations, and we will propose a testable working model whereby LRRK2-related PD may present with variable LB pathology.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above the age of 60 years, and 5% of individuals over the age of 85 (Reeve et al, 2014)
This is consistent with the idea that PD can be attributed to a combination of genetic, environmental and age-related factors, and indicates that the G2019S leucine-rich repeat kinase 2 (LRRK2) variant serves as an ideal model system to investigate mechanisms underlying sporadic PD pathogenesis (Ren et al, 2019)
In the case of PD due to mutations in LRRK2, structural and functional lysosomal alterations may arise due to impaired lysosome reformation in a manner dependent on Rab7a, with lysosomal identity and function further compromised in the context of additional lysosomal stress
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above the age of 60 years, and 5% of individuals over the age of 85 (Reeve et al, 2014). Point mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial, autosomal-dominant Parkinson’s disease (PD; Brice, 2005; Di Fonzo et al, 2006; Lesage et al, 2006; Ozelius et al, 2006), and sequence variations in LRRK2 are known to modify PD risk, indicating that it plays a role in the most common sporadic form of the disease (Gilks et al, 2005; Nalls et al, 2014). In contrast to all other pathogenic LRRK2 mutations which are highly penetrant, the G2019S variant displays significantly reduced penetrance which increases with age (Goldwurm et al, 2007; Gasser, 2015; Christensen et al, 2018) This is consistent with the idea that PD can be attributed to a combination of genetic, environmental and age-related factors, and indicates that the G2019S LRRK2 variant serves as an ideal model system to investigate mechanisms underlying sporadic PD pathogenesis (Ren et al, 2019). We will summarize current knowledge about the link between pathogenic LRRK2 activity, Rab phosphorylation and concomitant lysosomal deficits, which may contribute to cell death associated with LRRK2-related PD in either the absence or presence of α-synuclein pathology
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