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

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alpha-Synuclein (αSyn) aggregation is implicated in Parkinson's disease (PD) pathogenesis.
• Fatty acid-binding protein 3 (FABP3) exacerbates αSyn aggregation and neurotoxicity.
• Previous in vitro studies showed a C-terminal αSyn decoy peptide inhibits FABP3-induced αSyn aggregation.

Purpose of the Study:

• To validate the therapeutic potential of αSyn-derived peptides in an in vivo mouse model of PD.
• To investigate the effects of these peptides on αSyn neurotoxicity and behavioral deficits.
• To explore the mechanism by which peptides interfere with αSyn and FABP3 interactions.

Main Methods:

• Mice were injected with αSyn preformed fibrils (PFFs) into the olfactory bulb (OB).
• Nasal administration of peptides was initiated one week post-injection.
• αSyn phosphorylation, neuronal damage, and αSyn-FABP3 interactions were assessed via immunostaining and co-immunoprecipitation.

Main Results:

• PFF-injected mice exhibited memory loss but not motor deficits.
• Peptide treatment prevented memory impairment and reduced αSyn phosphorylation and neuronal death in the OB.
• Peptides successfully entered the OB via the nasal cavity and inhibited αSyn-FABP3 oligomer formation.

Conclusions:

• αSyn decoy peptides are effective in preventing memory deficits in a PD mouse model.
• The peptides act by suppressing toxic αSyn-FABP3 oligomer accumulation.
• This αSyn decoy peptide strategy offers a novel therapeutic avenue for synucleinopathies.