α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss

Abstract

Aims We previously found that a decoy peptide derived from the C‐terminal sequence of α‐Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid‐binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn‐derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)‐injected mouse model of Parkinson's disease (PD). Methods Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2‐week intervals post‐injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co‐immunoprecipitation. Results αSyn PFF‐injected mice showed significant memory loss but no motor function impairment. Long‐term nasal treatment with peptides effectively prevented memory impairment. In peptide‐treated αSyn PFF‐injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn‐FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3. Conclusions Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn‐FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.

Pathogenic Impact of Fatty Acid-Binding Proteins in Parkinson’s Disease—Potential Biomarkers and Therapeutic Targets

“…It was found that FABP3 can bind to α-synuclein in a 1:1 ratio, promoting α-synuclein-FABP3 aggregate formation [115]. Consequently, we attempted to create a drug that could inhibit the interaction between FABP3 and α-synuclein [126,142].…”

“…The FABP3 ligand effectively prevents the degeneration of dopaminergic neurons and restores motor dysfunction to a healthy level in a Parkinson's disease mouse model [126]. Additionally, an α-synuclein mimicking peptide that inhibits the binding and aggregate formation of α-synuclein-FABP3 is capable of restoring memory and learning abilities in a Parkinson's disease dementia mouse model [142]. This peptide has the potential to alleviate α-synuclein phosphorylation, which links to neurotoxicity.…”

Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson’s Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique

“…Notably, FABP3 colocalizes with α-synuclein aggregates and contributes to mitochondrial dysfunction and the loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis [4,9]. Encouragingly, the inhibition of FABP3 using small-molecule ligands and peptides has demonstrated the ability to prevent FABP3-induced neurotoxicity [6,[10][11][12]. These findings highlight FABP3 as a potential target for addressing α-synuclein pathology and its associated effects.…”

The 75–99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation

“…Peptides are well suited to be evaluated as potential aggregation inhibitors and/or potential α-synuclein disaggregators, thus reversing the ongoing neurodegeneration [15]. Most of the peptides proposed are fragments/or mutated fragments of the NAC (nonamyloid-β-component) domain as well as of the N-terminus of the α-synuclein or pre-NAC domain [16][17][18], the NAC-region and C-terminal region from a peptide library spanning the entire α-synuclein sequence [19], a larger library [20,21] and purified from natural sources, such as the peptide YIAEDAER from the marine snail Neptunea arthritica cumingii [22]. Established by segmenting all proteins deposited in the Protein Data Bank, the database proposed in [23] is centered on sequences adopting β-structures, specifically those identical or very similar to the regions of α-synuclein that are involved in aggregation.…”