LRRK2: Molecular Mechanisms in Parkinson’s Disease

The structural basis for LRRK2's activation and autoinhibition.

A unified framework for understanding LRRK2 regulation with broad therapeutic implications is provided, showing that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition.

LRRK2 G2019S reprograms innate and adaptive immunity to drive context-dependent host defense outcomes

Introduction Parkinson’s disease (PD) is increasingly recognized as a neurological disorder characterized not only by neurodegeneration but also by chronic immune dysregulation across the lifespan. Although the initiating events underlying PD remain unclear, accumulating evidence suggests that inflammatory processes may contribute to disease susceptibility and progression. Mutations in leucine-rich repeat kinase 2 (LRRK2), particularly the gain-of-function G2019S variant, represent the common genetic cause of familial PD and have been implicated in immune regulation and infection susceptibility. To date, most research has focused on the effect of LRRK2 mutation in neurons and the contributions of G2019S-mediated kinase activity to neuronal toxicity, leaving the role of G2019S-mediated kinase activity in immune cell homeostasis and its contribution to PD pathogenesis largely unresolved. Methods Here, we used murine overexpression models of wildtype and G2019S variant of mouse Lrrk2 to examine how Lrrk2 G2019S shapes host defense across viral and bacterial infection models. We tested systemic sepsis and Escherichia coli infection to examine bacterial clearance. We followed up by testing macrophage responses to intracellular (Listeria monocytogenes) or primarily extracellular (Pseudomonas aeruginosa) bacteria. Finally, tested antibody-mediated immunity using influenza and cytotoxic T cell-mediated immunity using lymphocytic choriomeningitis virus (LCMV) infection. Results We found that Lrrk2 G2019S overexpression enhanced survival and bacterial clearance during P. aeruginosa lung infection, whereas the same genotype worsened outcomes in polymicrobial sepsis, with increased mortality, pulmonary myeloid infiltration and a hematopoietic cell-intrinsic phenotype. During L. monocytogenes infection, Lrrk2 G2019S selectively reduced non-classical monocytes without altering disease progression. In influenza and LCMV infection, G2019S altered antigen-specific CD8+ T cell distribution without major changes in cell memory responses clinical severity. Discussion Together, these data show that Lrrk2 G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner, uncoupling inflammatory magnitude from effective host defense. These results and previous work support a model in which the G2019S LRRK2 variant contributes to maladaptive inflammatory responses to specific infection challenges, providing insight into how lifetime immune perturbations may intersect with genetic susceptibility to influence lifetime infection risk.

The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages

ABSTRACT Variants in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, yet how these variants alter immune cell function remains unclear. Because LRRK2 is activated by lysosomal damage in macrophages, we investigated how the pathogenic G2019S variant affects macrophage responses to lysosomal damage. Here, we show that LRRK2 G2019S has an effect during lysosomal damage through kinase-dependent and kinase-independent mechanisms. Phosphoproteomic analysis revealed that lysosomal damage induces selective rewiring of LRRK2-dependent Rab GTPase phosphorylation, characterised by increased Rab12 phosphorylation and reduced Rab35 phosphorylation without global kinase hyperactivation. Strikingly, LRRK2 G2019S macrophages showed increased susceptibility to apoptosis following lysosomal damage. This increase in cell death occurred independently of the kinase activity, indicating a distinct kinase-independent role of LRRK2 in regulating cell survival. We generated isogenic induced pluripotent stem cells from patients carrying the LRRK2 G2019S variant and confirmed that LRRK2 G2019S macrophages are more susceptible to cell death in a kinase-independent manner. Together, our findings support a model in which the LRRK2 G2019S variant selectively changes the phosphorylation of Rab GTPases in macrophages and increases cell death after lysosomal damage in macrophages.

Glial control of extracellular α-synuclein propagation in LRRK2 Parkinson's disease.

G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.

The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.

Dynamic structural profiling of PINK1 mutations (T313M and L347P) reveals a vital molecular perturbation namely phospho-Serine 65 ubiquitin recognition point in mitophagy mediated autosomal recessive Parkinson’s disease (ARPD)

These findings establish a mechanistic link between mutation-induced structural dynamics and impaired PINK1–ubiquitin recognition at Ser65, providing a mutation-specific framework for understanding early mitophagy impairment in ARPD and supporting future molecular assessment and targeted therapeutic development.