Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson's Disease?

Abstract

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson's disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD.

Keywords: Parkinson’s disease; astrocytes; glial cells; inflammation; leucine rich-repeat kinase 2; lysosomes; microglia.

Figure 1

Domain structure of LRRK2. Sites of representative pathological mutations are indicated [7]. G2385R is considered a risk variant in Asian races [7]. LRRK2, leucine rich-repeat kinase 2; ARM, armadillo domain; ANK, ankyrin repeat domain; LRR, leucine-rich repeat domain; ROC, Ras of complex protein domain; COR, carboxyl-terminal of ROC domain; WD40, WD 40 domain; aa, amino acids.

Figure 2

Overview of LRRK2 research, research problems, and issues to be resolved. In humans, risk SNPs have been found in Crohn’s disease as well as Parkinson’s disease. Currently, the impact of Crohn’s disease-associated SNPs on LRRK2 function is not clear [71,72]. Many in vivo models do not exhibit the pathological changes observed in Parkinson’s disease. However, LRRK2 knockout rodent models are an excellent tool to study the physiological function of LRRK2. In vitro models are superior for analysis at the organelle and molecular levels but have the disadvantage of not being able to reproduce the normal aging process and the brain environment. The results obtained from each of these models should be assessed in light of these considerations. The studies to which this review refers are indicated in red [11,12,13,14,73]. C. elegans and Drosophila models are excellent for molecular genetic analysis but will not be mentioned here. EV, extracellular vesicle.

Figure 3

Reported roles of LRRK2 in astrocytes. (A) LRRK2 accumulates in membrane-damaged lysosomes and phosphorylates downstream Rab10, causing lysosomal tubulation and budding [23]. (B) Microtubule-dependent kinesin–ARL8B and dynein–JIP4 motors move the lysosomes to the peripheral and perinuclear regions, respectively [89]. Rab10 is preferentially phosphorylated in the perinuclear lysosomes by LRRK2 (A), whereas Rab12 is phosphorylated in both the perinuclear and the peripheral lysosomes. (C) Impairment of chaperone-mediated autophagy by LRRK2 G2019S leads to α-synuclein accumulation in astrocytes [12]. Astrocyte-derived pathogenic α-synuclein is transported into dopaminergic neurons [12]. On the other hand, phagocytic defects of α-synuclein fibrils due to decreased annexin A2 by LRRK2 G2019S are also suggested [91]. (D) Compared to normal astrocytes, LRRK2 G2019S astrocytes have smaller MVBs, along with the accumulation of phospho-S129 α-synuclein and lower EV release. The alteration of EV biogenesis in LRRK2 G2019S astrocytes induces dendritic shortening and cell death in dopaminergic neurons [13]. MVB, multivesicular body; EV, extracellular vesicle; P, phosphorylation.

Figure 4

Reported roles of LRRK2 in microglia. (A) LRRK2 negatively regulates the migration of microglia through the suppression of focal adhesion kinase (FAK) via phosphorylation [117]. (B) LRRK2 phosphorylates and stabilizes WAVE2, inducing the positive regulation of microglial phagocytosis [54]. (C) LRRK2 kinase activity is required for the mobilization of Rab8a and Rab10 to phagosomes, which leads to phagosome maturation [109]. (D) LRRK2 accumulates and recruits Rab8 and Rab10 under lysosomal stress in a Rab29-dependent manner, which causes the extracellular release of the lysosomal contents [22]. (E) NFATc2 is phosphorylated by LRRK2 in microglia exposed to α-synuclein and then translocated to the nucleus for transcriptional regulation [14]. (F) Nuclear migration of NFATc2 is inhibited in LRRK2 G2019S iPS cell-derived microglia [15]. (G) LRRK2 pathogenic mutants sequester Rab8 to the lysosomes via phosphorylation, directing the transferrin-mediated iron endocytosis pathway from lysosomal recycling to degradation [16]. As a result, iron deposition is accelerated [16]. (H) Microglia that have taken up excess amounts of α-synuclein fibrils transport these fibrils to other microglia through F-actin-associated nanotubes [31]. P, phosphorylation.