Development of a targeted BioPROTAC degrader selective for misfolded SOD1

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Misfolded protein accumulation is central to neurodegenerative diseases like ALS.
• Targeting these dynamic misfolded proteins therapeutically remains a significant challenge.
• Superoxide dismutase 1 (SOD1) mutations are linked to familial ALS, leading to toxic protein aggregation.

Purpose of the Study:

• To develop and validate a novel therapeutic strategy targeting misfolded SOD1 variants in ALS.
• To assess the efficacy of a biological proteolysis targeting chimera (BioPROTAC) in degrading toxic SOD1 species.
• To evaluate the therapeutic potential of BioPROTACs in delaying neurodegeneration in an ALS mouse model.

Main Methods:

• Designed and screened SOD1-specific intrabodies and E3 ligases for optimal BioPROTAC construction.
• Utilized CRISPR/Cas9 technology to generate a BioPROTAC transgenic mouse line.
• Assessed disease progression, motor neuron survival, SOD1 aggregation, and neuromuscular junction integrity in SOD1^G93A^ mice.

Main Results:

• Identified a BioPROTAC capable of degrading multiple disease-associated SOD1 variants and preventing cellular aggregation.
• Demonstrated that BioPROTAC expression in transgenic mice significantly delays disease progression in the SOD1^G93A^ ALS model.
• Observed protection of motor neurons, reduced insoluble SOD1, and preserved neuromuscular junctions in treated mice.

Conclusions:

• BioPROTACs represent a viable therapeutic platform for targeted degradation of neurotoxic misfolded proteins.
• This approach shows promise for treating neurodegenerative diseases like ALS by clearing disease-specific protein aggregates.
• Further development of BioPROTACs could offer a new avenue for treating proteinopathies.