LRRK2 Ablation Attenuates Αlpha-Synuclein-Induced Neuroinflammation Without Affecting Neurodegeneration or
Anke Van der Perren1, Diego Cabezudo1, Géraldine Gelders1
1Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49 bus 1023, 3000, Leuven, Belgium.
Abstract:
The development of disease-modifying therapies for Parkinson's disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson's disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein-induced neurotoxicity and neuroinflammation in preclinical Parkinson's disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector-mediated α-synuclein-based Parkinson's disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein-induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein-induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4+ and CD8+ T cell infiltration. This observed lack of protection against α-synuclein-induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson's disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events.
Insights
Targeting Leucine-rich repeat kinase 2 (LRRK2) did not prevent alpha-synuclein toxicity in Parkinson's models. However, LRRK2 loss reduced neuroinflammation, suggesting a complex role in Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Pathology
- Pharmacology
Background:
- Parkinson's disease (PD) pathogenesis involves Leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein.
- The precise relationship between LRRK2 and alpha-synuclein in PD remains unclear.
- Previous studies on LRRK2's role in alpha-synuclein-induced neurotoxicity yielded conflicting results.
Purpose of the Study:
- To investigate the functional interaction between alpha-synuclein and LRRK2.
- To evaluate the therapeutic potential of targeting LRRK2 in PD models.
- To explore the impact of LRRK2 loss or inhibition on alpha-synuclein pathology and neuroinflammation.
Main Methods:
- Utilized viral vector-mediated alpha-synuclein models of early- and late-stage PD.
- Assessed effects of total LRRK2 protein loss (ablation).
- Evaluated pharmacological LRRK2 kinase inhibition using MLi-2.
Main Results:
- LRRK2 ablation or MLi-2 treatment did not significantly alter alpha-synuclein-induced motor deficits, dopaminergic cell loss, or alpha-synuclein pathology.
- Absence of LRRK2 led to significantly reduced microglial activation and T cell infiltration in response to alpha-synuclein.
- Neuroinflammatory changes were modulated by LRRK2 status, independent of direct neuroprotection.
Conclusions:
- Targeting LRRK2 kinase activity may not be a viable strategy for mitigating alpha-synuclein toxicity in PD.
- LRRK2 plays a significant role in regulating neuroinflammatory responses in the context of alpha-synuclein pathology.
- Further research is needed to elucidate the link between LRRK2, neuroinflammation, and PD progression.
