By Ana Espino | Published on April 8, 2026 | 4 min readParkinson’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.
