Dual-function PROTAC suppresses ferroptosis and restores neuronal function via brain-targeted delivery

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) is a promising therapeutic strategy.
• Effective brain-specific protein degradation for neurodegenerative diseases remains a significant challenge.
• Ferroptosis, a form of regulated cell death, plays a critical role in neurodegeneration.

Purpose of the Study:

• To develop a dual-function PROTAC (dACSL4) for brain-preferred protein degradation and ferroptosis suppression.
• To investigate the therapeutic potential of dACSL4 delivered via nose-to-brain administration.
• To evaluate the efficacy of dACSL4 in a Parkinson's disease model.

Main Methods:

• Design and synthesis of a dual-function PROTAC, dACSL4, targeting acyl-CoA synthetase long-chain family member 4 (ACSL4) and activating peroxisome proliferator-activated receptor γ (PPARγ).
• Development of biodegradable lipid nanoparticles (BAmP-TK12) for intranasal delivery of dACSL4.
• Assessment of dACSL4's efficacy in protecting neurons against ferroptosis in vitro and in vivo.
• Evaluation of dACSL4's therapeutic effects in a mouse model of Parkinson's disease.

Main Results:

• dACSL4 selectively degrades ACSL4 and activates PPARγ, coordinating lipid metabolism and oxidative stress to suppress ferroptosis.
• dACSL4 demonstrated up to 30-fold greater protection against ferroptosis than conventional inhibitors.
• Intranasal delivery of dACSL4 via BAmP-TK12 achieved brain-preferred ACSL4 degradation and PPARγ activation.
• Treatment reduced lipid peroxidation, preserved dopaminergic neurons, and improved motor function in a Parkinson's disease model.

Conclusions:

• dACSL4 represents a novel dual-function degrader with significant potential for treating neurodegenerative diseases.
• Nose-to-brain delivery of dACSL4 offers an effective strategy for brain-preferred targeted protein degradation.
• This modular approach holds promise for developing new therapies targeting ferroptosis in neurodegeneration.