Targeting α-synuclein translation: Novel PROTEIMERs as 5'-UTR directed inhibitors

Area of Science:

• Neuroscience
• Molecular Biology
• Drug Discovery

Background:

• Alpha-Synuclein aggregation characterizes neurodegenerative diseases like Parkinson's.
• Targeting alpha-Synuclein protein is challenging due to its dynamic nature.
• Alpha-Synuclein mRNA presents a viable therapeutic target.

Purpose of the Study:

• Develop protein-based RNA-binding therapeutics (PROTEIMERs).
• Target the 5' untranslated region (UTR) of alpha-Synuclein mRNA.
• Inhibit alpha-Synuclein translation to reduce protein levels.

Main Methods:

• High-throughput phage display for PROTEIMER identification.
• Surface plasmon resonance (SPR) for binding affinity assessment.
• In vitro RNA degradation assays with RNase-fused PROTEIMERs.

Main Results:

• Identified three high-affinity PROTEIMERs targeting alpha-Synuclein 5'UTR.
• Structural predictions confirmed specific RNA interactions.
• RNase-fused PROTEIMERs induced targeted alpha-Synuclein mRNA degradation.

Conclusions:

• Demonstrated feasibility of engineered protein therapeutics for alpha-Synuclein mRNA.
• PROTEIMERs offer a novel strategy for reducing alpha-Synuclein.
• Potential to mitigate neurodegenerative disease progression in PD, LBD, and AD.