A Single Chain Fragment Variant Binding Misfolded Alpha-Synuclein Exhibits Neuroprotective and Antigen-Specific...

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Alpha synuclein (αSyn) misfolding is central to synucleinopathies like Parkinson's disease (PD).
• Mechanisms include direct neurotoxicity, neuroinflammation, and pathological αSyn spread.
• Previous immunotherapy trials in PD showed limited success.

Purpose of the Study:

• To develop and evaluate a single-chain variable fragment (scFv) antibody targeting αSyn.
• To assess its efficacy in preclinical models of PD.

Main Methods:

• Selected an αSyn-binding scFv (sMB08) from phage display libraries.
• Tested sMB08's ability to protect neurons, modulate microglial uptake, and degrade misfolded αSyn.
• Evaluated sMB08's impact on αSyn aggregation, spreading, and seeding in vivo.

Main Results:

• sMB08 protected neurons from αSyn toxicity and reduced microglial uptake.
• It demonstrated anti-inflammatory effects, reducing neuroinflammation and autoimmunity.
• Intranasal sMB08 treatment in PD models improved motor function and preserved dopaminergic neurons.

Conclusions:

• sMB08 targets both αSyn oligomers and pre-formed fibrils (PFF).
• Its small size facilitates brain penetration and avoids non-specific inflammation.
• sMB08 represents a promising therapeutic strategy for PD and related synucleinopathies.