Peripheral inflammation mediates midbrain Lrrk2 kinase activity via Rab32 expression
Biorxiv : the Preprint Server for Biology
|March 18, 2026
Summary
Peripheral inflammation triggers Rab32 expression in microglia, activating Lrrk2 kinase. This pathway links inflammation to Parkinson's disease risk, highlighting Rab32/Tfe3 as potential therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) increase Parkinson's disease (PD) risk, but incomplete penetrance indicates other factors are involved.
- Rab32 Ser71Arg was recently identified as a Mendelian gene for PD, suggesting a role for Rab32 in disease pathogenesis.
Purpose of the Study:
- To establish Rab32 as a mediator linking peripheral inflammation to Lrrk2 activation in Parkinson's disease.
- To investigate the role of Tfe3 in regulating Rab32 expression and Lrrk2 activity during inflammation.
Main Methods:
- In vivo studies using lipopolysaccharide (LPS) to induce peripheral inflammation in mice.
- Analysis of Rab32 expression in microglia and dopaminergic neurons.
- Utilizing human induced pluripotent stem cell-derived microglia to assess species-conserved responses.
- Promoter analysis to identify regulatory elements controlling Rab32 expression.
- Investigating the nuclear translocation of Tfe3 in response to inflammation.
Main Results:
- Peripheral LPS-induced inflammation selectively increased Rab32 expression in midbrain microglia, correlating with Lrrk2 kinase activity.
- LPS induced Rab32 expression in human microglia, indicating a conserved inflammatory response.
- Tfe3 was identified as a key driver of LPS-induced Rab32 expression and Lrrk2 activation.
- Tfe3 nuclear translocation in microglia during inflammation enhanced Rab32 expression and Lrrk2 activity.
- Knockdown of Tfe3 mitigated inflammation-induced Rab32 expression and Lrrk2 activation.
Conclusions:
- Rab32 acts as a crucial mediator linking peripheral inflammation to Lrrk2 activation in Parkinson's disease.
- The Rab32/Tfe3 pathway represents a novel mechanism by which inflammation modulates Lrrk2 activity.
- Targeting Rab32 and Tfe3 offers a potential therapeutic strategy for neuroprotection in Parkinson's disease.
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