TITLE:
Brain-Specific PP1/LRRK2 Interaction-Tageting Peptides as a Novel Strategy for Parkinson’s Disease Treatment
AUTHORS:
Severine Loisel, Fanny Petit, Gwenaelle Auregan, Martine Guillermier, Marjorie Benfissa, Pauline Gipchtein, Asma Touffeil Mohamed, Kristina Posnograjeva, Tambet Teesalu, Romina Aron Badin, Angelita Rebollo
KEYWORDS:
Parkinson’s Disease, BBB, Therapeutic Peptides, Protein-Protein Interaction, PP1, LRRK2
JOURNAL NAME:
Advances in Parkinson's Disease,
Vol.15 No.3,
September
22,
2026
ABSTRACT: The LRRK2 kinase has emerged as a priority therapeutic target due to its well-documented role in Parkinson-s diseases (PD). One of LRRK2’s 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 Parkinson’s disease.