LRRK2: the key role of lysosomes in parkinson’s disease?

By Ana Espino | Published on April 8, 2026 | 4 min read


Parkinson’s disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of protein aggregates. Despite therapeutic advances, the underlying molecular mechanisms remain only partially understood.

The protein LRRK2 (leucine-rich repeat kinase 2) is now recognized as a central player. Mutations that increase its kinase activity are implicated in both familial and sporadic forms of the disease. However, the regulation of this activity and its exact role in pathophysiology are still not fully clarified.

Recent research suggests a close link between LRRK2, lysosomes, and cellular stress mechanisms, opening new perspectives. This review, published in 2025 in Current Opinion in Cell Biology, aims to synthesize recent advances in LRRK2 regulation—particularly through Rab GTPases and lysosomal damage pathways—to better understand their involvement in Parkinson’s disease.

Is LRRK2 a sensor of lysosomal stress?

This review is based on recent experimental data from cellular and animal models, as well as human genetic analyses. It highlights several converging mechanisms regulating LRRK2 activity.

First, Rab GTPases play a central role. LRRK2 phosphorylates several Rab proteins, which act both as substrates and activators, promoting its recruitment to cellular membranes. This mechanism follows a feed-forward activation loop, locally amplifying kinase activity.

Second, lysosomal stress appears to be a key driver. Various stimuli—including chemical agents, infections, or ionic imbalances—induce the recruitment of LRRK2 to damaged lysosomes, significantly increasing its activity. This positions LRRK2 as a dynamic sensor of cellular damage.

A key finding is the identification of the CASM pathway (conjugation of ATG8 to single membranes). Different stress signals converge on this pathway, leading to GABARAP lipidation and recruitment of LRRK2 to the lysosomal membrane. This direct interaction represents a unifying activation mechanism.

Moreover, LRRK2 interacts with other cellular systems involved in lysosomal repair, including the ESCRT pathway and endoplasmic reticulum–lysosome contact sites. Proteins associated with Parkinson’s disease, such as VPS13C, are also involved in these processes, suggesting convergence of pathogenic pathways.

Finally, LRRK2 plays a role in innate immunity, particularly in macrophages. Its activation during infections promotes defense mechanisms, but chronic activation may contribute to neurodegeneration.

A key target still to be deciphered

Parkinson’s disease involves complex mechanisms combining lysosomal dysfunction and inflammation. This study aimed to clarify the role of LRRK2 in these processes.

The findings show that LRRK2 acts as an integrator of lysosomal stress signals, through interactions with Rab proteins and the CASM pathway, contributing to the regulation of cellular responses to damage.

However, several limitations remain, including an incomplete understanding of LRRK2’s exact functions in vivo and differences across cell types, particularly in the brain.

These findings open major perspectives. Targeting LRRK2 and lysosomal pathways could represent an innovative therapeutic strategy. Ultimately, a better understanding of these mechanisms may enable the development of personalized approaches to slow or prevent the progression of Parkinson’s disease.  

Read next: Gene therapy: a turning point for parkinson’s disease?

About the author – Ana Espino
PhD in Immunology, specialized in Virology  
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.