Brain-specific PP1/LRRK2 interaction-targeting peptides as a novel strategy for Parkinson's disease treatment

Rebollo, A.; Loisel, S.; Petit, F.; Auregan, G.; Guillermier, M.; Benfissa, M.; Gipchtein, P.; Touffeil Mohamed, A.; Posnograjeva, K.; Teesalu, T.; Aron Badin, R.

doi:10.64898/2026.07.27.740889

bioRxiv · 10.64898/2026.07.27.740889

Brain-specific PP1/LRRK2 interaction-targeting peptides as a novel strategy for Parkinson's disease treatment

Rebollo, A.·Loisel, S.·Petit, F.·Auregan, G.·Guillermier, M.·Benfissa, M.·Gipchtein, P.·Touffeil Mohamed, A.·Posnograjeva, K.·Teesalu, T.·Aron Badin, R.

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Abstract

The LRRK2 kinase has emerged as a priority therapeutic target due to its well-documented role in Parkinson-s diseases (PD). One of LRRK2s key partners is the phosphatase PP1, which dephosphorylates LRRK2. Therefore, modulating this protein/protein interaction represents a promising therapeutic strategy for PD. We have developed a bi-functional peptide, PEP 3, capable of crossing the blood-brain barrier (BBB) and disrupting the LRRK2/PP1 interaction. In vitro competition assays confirmed that PEP 3 specifically targets this interaction. The in vivo imaging demonstrated that the peptide remains detectable in the mouse brain up to 6 hours or retro-orbital vein post-injection. The PEP 3 peptide does not show chronic toxicity in CD1 mice and is resistant to degradation by mouse, human, dog and monkey serum proteases. In mouse models overexpressing alpha-synuclein, repeated intraperitoneal injections of PEP 3 for 15 and 30 days were well tolerated. Immunohistochemistry revealed a significant reduction of dopaminergic cell death in the substantia nigra, and quantification of phosphorylated pathological alpha-synuclein showed decreased levels in the PEP 3-treated group compared to controls. These findings support the potential of PEP 3 as a therapeutic agent for Parkinsons disease.

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Rebollo, A., Loisel, S., Petit, F., Auregan, G., Guillermier, M., Benfissa, M., Gipchtein, P., Touffeil Mohamed, A., Posnograjeva, K., Teesalu, T., Aron Badin, R.. 2026-07-29. Brain-specific PP1/LRRK2 interaction-targeting peptides as a novel strategy for Parkinson's disease treatment. https://doi.org/10.64898/2026.07.27.740889

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