Brain-Specific PP1/LRRK2 Interaction-Tageting Peptides as a Novel Strategy for Parkinson’s Disease Treatment
Abstract
The LRRK2 kinase has emerged as a priority therapeutic target due to its welldocumented 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.
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BibTeX
@article{loisel2026brainspecific,
title = {{Brain-Specific PP1/LRRK2 Interaction-Tageting Peptides as a Novel Strategy for Parkinson’s Disease Treatment}},
author = {Severine Loisel and Fanny Petit and Gwenaelle Auregan and Martine Guillermier and Marjorie Benfissa and Pauline Gipchtein and Asma Touffeil Mohamed and Kristina Posnograjeva and Tambet Teesalu and Romina Aron Badin and Angelita Rebollo},
journal = {Advances in Parkinson's Disease},
year = {2026},
month = aug,
doi = {10.4236/apd.2026.153003},
url = {https://cnrs.hal.science/hal-05798064v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Brain-Specific PP1/LRRK2 Interaction-Tageting Peptides as a Novel Strategy for Parkinson’s Disease Treatment
AU - Severine Loisel
AU - Fanny Petit
AU - Gwenaelle Auregan
AU - Martine Guillermier
AU - Marjorie Benfissa
AU - Pauline Gipchtein
AU - Asma Touffeil Mohamed
AU - Kristina Posnograjeva
AU - Tambet Teesalu
AU - Romina Aron Badin
AU - Angelita Rebollo
PY - 2026
DA - 2026/08/31
JO - Advances in Parkinson's Disease
DO - 10.4236/apd.2026.153003
UR - https://cnrs.hal.science/hal-05798064v1
AB - The LRRK2 kinase has emerged as a priority therapeutic target due to its welldocumented 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.
SN - 2169-9712
SN - 2169-9720
ER -