Abstract
The leucine-rich repeat kinase 2 (LRRK2), the most common causative gene for autosomal-dominant familial Parkinson’s disease, encodes a large protein kinase harboring multiple characteristic domains. LRRK2 phosphorylates a set of Rab GTPases in cells, which is enhanced by the Parkinson-associated LRRK2 mutations. Accumulating evidence suggests that LRRK2 regulates intracellular vesicle trafficking and organelle maintenance including Golgi, endosomes and lysosomes. Furthermore, genetic knockout or inhibition of LRRK2 cause lysosomal abnormalities in rodents and primates, and cells from Parkinson’s patients with LRRK2 mutations also exhibit altered lysosome morphology. Cell biological studies on LRRK2 in a diverse cellular context further strengthen the potential connection between LRRK2 and regulation of the endolysosomal system, part of which is mediated by Rab phosphorylation by LRRK2. We will focus on the latest advances on the role of LRRK2 and Rab in relation to the endolysosomal system, and discuss the possible link to the pathomechanism of Parkinson’s disease.
Highlights
Mutations in leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal-dominant forms of Parkinson’s disease (PD) (Paisan-Ruiz et al, 2004; Zimprich et al, 2004)
The link of LRRK2 to sporadic PD has been suggested by a set of genome-wide association studies (GWAS) where common variants around LRRK2 gene have been identified as a risk factor of PD (Satake et al, 2009; Simón-Sánchez et al, 2009; Lill et al, 2012)
Ever since LRRK2 has been identified as a major PD gene, much effort has been directed toward unraveling the cellular roles of
Summary
Mutations in leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal-dominant forms of Parkinson’s disease (PD) (Paisan-Ruiz et al, 2004; Zimprich et al, 2004). A majority of familial PD patients harboring LRRK2 mutation display an accumulation of Lewy bodies in affected brain lesions, a range of heterogeneity (i.e., some cases are Lewy body predominant, while others exhibit tau deposits or lack specific intraneuronal inclusions) characterizes the neuropathology of LRRK2 mutant PD (Khan et al, 2005; Kalia et al, 2015). The link of LRRK2 to sporadic PD has been suggested by a set of genome-wide association studies (GWAS) where common variants around LRRK2 gene have been identified as a risk factor of PD (Satake et al, 2009; Simón-Sánchez et al, 2009; Lill et al, 2012). Elucidating the role of LRRK2 in pathological as well as physiological situations may provide hints for the establishment of rational strategy to treat PD
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