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.
Show 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.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Structural basis of epitope recognition by anti-alpha synuclein antibodies MJFR14-6-4-2 95%
- Neuroprotection of low dose carbon monoxide in Parkinson's disease models commensurate with the reduced risk of Parkinson's among smokers 93%
- High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescuespathological phenotypes in a Patient-Derived Model of Parkinson's Disease 93%
Similar papers in this journal
- Selection of single domain anti-transferrin receptor antibodies for blood-brain barrier transcytosis using a neurotensin based assay and histological assessment of target engagement in a mouse model of Alzheimer's related amyloid-beta pathology 95%
- Development of an orally-administrable tumor vasculature-targeting therapeutic using annexin A1-binding D-peptides 95%
- Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration 94%
Similar papers in this journal
- Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke 92%
- Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System 92%
- RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice 91%
Similar papers in this journal
- Identification of a cardiac glycoside exhibiting favorable brain bioavailability and potency for reducing levels of the cellular prion protein 94%
- The bacterial amyloids phenol soluble modulins from Staphylococcus aureus catalyze alpha-synuclein aggregation 92%
- Live cell imaging of single neurotrophin receptor molecules on human neuron in Alzheimer's disease 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.