Pathway for Parkinson disease.

Parkinson disease (PD) is a common neurodegenerative disease with unknown etiology. PD is commonly referred to as a “motor disease,” reflecting its clinical symptoms, including resting tremors of extremities, muscular rigidity, shuffling gait, stoop posture, and bradykinesia (1). The underlying pathology of PD is progressive neuronal loss, particularly in the substantia nigra pars compacta (SNc), and the presence of abnormal protein-rich aggregates—known as Lewy bodies—in the remaining neurons (2). The loss of dopaminergic neurons in the SNc, leading to dopamine deficiency, is believed to be responsible for the motor and nonmotor symptoms, including orthostatic hypotension, mood disorders, sleep disorder, and loss of sense of smell. Dopamine replacement therapy provides symptomatic relief, but disease progression continues unabated. Therefore, there is a need for understanding the mechanisms of PD to aid the development of more effective therapeutics. This endeavor is fueled by genetic discoveries in the past two decades that identified a number of genes associated with rare inheritable PD, including SNCA, Parkin/PRKN, DJ-1/Park7, PINK1, and LRRK2 (leucine-rich repeat kinase 2) (3). The push now is to understand the functions of these gene products and the biological pathways in which they operate. In PNAS, Beilina et al. identify a number of LRRK2 interactors whose jobs are to process endocytosed vesicles, thereby associating LRRK2 with the vesicle endocytosis pathways (4). Mutation in LRRK2 is a common cause of PD (5). LRRK2 is a large (2,527 amino acids) multidomain protein consisting of at least five putative domains (Fig. 1A) (6). The catalytic region consists of three of those domains: A Ras-like GTPase domain called Ras of complex proteins (ROC) followed by a domain called C-terminal of ROC (COR), which is in turn followed by a kinase domain (Kinase). The mechanism of LRRK2 in PD pathogenesis remains unclear; however, the most common disease-associated mutation in LRRK2, G2019S, shows higher kinase activity than wild-type. Therefore, overactivation of LRRK2 kinase activity might be associated with disease pathogenesis (7). The tandem ROC-COR-Kinase arrangement suggests that their activitiesmight be coupled such that the GTPase activity of ROC might modulate the kinase activity. Indeed, several studies have shown that GTP binding to the ROC domain regulates the activity of the Kinase (8, 9). Moreover, PD-associated mutation in the ROC domain (R1441C) has been shown to have higher kinase activity (10), thus suggesting that mutations in the ROC domain also up-regulate LRRK2’s kinase activity. Flanking the catalytic tridomain region, including about 1,300 residues upstream of ROC and about 400 residues downstream of the Kinase domain, are predicted to encode protein–protein interaction domains, including a leucine-rich repeat domain (LRR), a seven– β-propeller structure called WD40, and likely other protein–protein domains upstream of the LRR domain. LRRK2 is equipped to perform multiple biochemical functions; in my group, we refer to it as the “Swiss Army Knife” protein. The presence of multiple protein–protein interaction domains in LRRK2 Fig. 1. (A) Cartoon presentation of LRRK2 showing multidomain structure. Termini and predicted domains labeled along approximate domain boundaries. Cartoon of domain structures were rendered using coordinates of homology models built based on other proteins with known structures. The N-terminus region preceding the LRR domain consists of sequence similarity to more than one additional protein–protein interaction domain, including HEAT [Huntingtin, elongation factor 3 (EF3), protein phosphatase 2A (PP2A), and the yeast kinase TOR1] repeats and Ankyrin repeats; however, their boundaries are more difficult to approximate. (B) A simplified drawing of the vesicular endocytosis pathway showing GAK/Hsc70 involvement in uncoating clathrin-coated vesicles. BAG5 might also be involved in the same process by interacting with Hsc70, and Rab7L1 functions in the retromer sorting process. LRRK2 interacts with all three proteins (GAK, BAG5, and Rab7L1); thus, the process of vesicular endocytosis, sorting, recycling, and degradation might be important in the pathogenesis of PD. Author contributions: Q.Q.H. wrote the paper.