The Multifaceted Role of LRRK2 in Parkinson's Disease

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein kinase intricately involved in the pathogeneses of various neurodegenerative diseases, particularly Parkinson's disease (PD). LRRK2 plays a pivotal role in mitochondrial function and cellular senescence by regulating key processes such as autophagy, oxidative stress, and protein aggregation. LRRK2 is also associated with ciliogenesis in regulating neuronal development. In addition, LRRK2 has been implicated as a putative mediator in neuroinflammation via promoting the reactivation of microglia and influencing cytokine production, a factor that may have therapeutic implications. Furthermore, mutations in LRRK2 have been found to impact the production of neurotrophic factors in astrocytes, the star-shaped glial cells of the central nervous system, thereby affecting neuronal health and contributing to the pathology of neurodegenerative diseases like PD. The multifaceted roles of LRRK2 in cellular senescence, interaction with LRS, neuroinflammation, the maintenance of mitochondria, and astrocyte function highlight its significance as a therapeutic target for neurodegenerative disorders.

Keywords: Parkinson’s disease; cellular senescence; ciliogenesis; leucine-rich repeat kinase 2; mitochondrial homeostasis; neuroinflammation; neurotrophic factor; translation.

Figure 1

The structure of LRRK2 and its cellular function. Leucine-rich repeat kinase 2 (LRRK2) protein is composed of armadillo repeat (ARM), ankyrin repeat (ANK), leucine-rich repeat (LRR), Ras-of-complex (ROC), c-terminal of ROC (COR), kinase (KIN), and WD40. LRRK2 has been implicated in cellular mechanisms such as mitochondrial dynamics, translation, protein quality control, neuroinflammation, astrocytic neurotrophic conditioning, and ciliogenesis.

Figure 2

The involvement of LRRK2 in mitochondrial dynamics and homeostasis. LRRK2-phosphorylated dynamin-related protein 1 (Drp1) and the interaction of LRRK2 with mitofusins (Mfn) or Parkin, the latter of which binds to PTEN-induced kinase 1 (PINK1), are related to mitochondrial dynamics. The LRRK2-mediated Erk1/2 pathway is linked to the activation of nuclear factor-like 2 (Nrf2), contributing to anti-oxidative stress responses and mitochondrial calcium transport. LRRK2 has also been demonstrated to be associated with the regulation of calcium channels in the plasma membrane.

Figure 3

The role of LRRK2 in translation. LRRK2 phosphorylates ribosomal protein S15 (RPS15), contributing to the mRNA translation process, and facilitates the translation of the 5′ untranslated region (5′ UTR), resulting in the upregulation of calcium channel expression. Furthermore, the phosphorylation of 4E-BP1 by LRRK2 enhances the eIF4E-mediated initiation of mRNA translation, thereby increasing protein aggregation and cellular stress. LRRK2 has also been demonstrated to promote autophagic failure via the phosphorylation of leucyl-tRNA synthetase (LRS). “P” with red letter in the triangle is the phosphorylation state of LRRK2.

Figure 4

The function of LRRK2 in protein quality control. LRRK2 has been demonstrated to impede the autophagy–lysosomal pathway by suppressing Beclin-1 and augmenting the phosphorylation of Rab GTPases, including Rab8, Rab 10, and Rab35. The elevation of LRRK2 kinase activity by specific mutations like G2019S and oxidative stress, such as that generated by rotenone, 6-hydroxydopamine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been shown to highly phosphorylate p53. Activation of p53 induces the activity of p21, and p53–p21 cell-cycle arrest axis drives cellular senescence via decreasing Rb phosphorylation and increasing senescence-associated beta-galactosidase (senescence-associated β-gal) in dopaminergic neurons, thereby aggravating autophagy–lysosomal impairment and α–synuclein aggregation.

Figure 5

The action of LRRK in neuroinflammation. LRRK2 enhances the expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukins, and nitric oxide (NO) via interactions with the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (p38 MAPK), and signal transducer and activator of transcription 3 (STAT3) in microglia. LRRK2-mediated phosphorylation of nuclear factor of activated T cells 2 (NFATc2), which is driven by the stimulation of toll-like receptors (TLRs) with neuron-released α-synuclein, has been shown to increase proinflammatory responses. LRRK2 promotes the release of interleukins via regulating NLR family CARD domain-containing protein 4 (NLRC4). These neuroinflammatory responses are responsible for the degeneration of dopaminergic neurons. Phosphorylation by LRRK2 is indicated by the blue line.

Figure 6

The effects of G2019S LRRK2 expression in astrocytes. G2019S LRRK2 expression has been demonstrated to reduce the release of nerve growth factor (NGF) and increase the secretion of TNF-α and interleukin-1beta (IL-1β) in astrocytes. The vesicle release process, which plays a crucial role in the communication between astrocytes and neurons, has been demonstrated to be altered by G2019S LRRK2 expression in astrocytes. Consequently, the failure of astrocytes to adequately maintain neural health by expressing G2019S LRRK2 has the potential to render dopaminergic neurons vulnerable.

Figure 7

The association of LRRK2 with cilia function and ciliogenesis. The phosphorylation of Rab8 and Rab10 by LRRK2 mutation has been demonstrated to disrupt ciliogenesis in neurons. LRRK2 also has been demonstrated to be associated with intraflagellar transport within the axoneme of cilia. Consequently, aberrant LRRK2 activity has the potential to modify the function of cilia in neural development and signal transduction.