Polymer-peptide conjugates prevent and disperse toxic dipeptide repeat aggregates implicated in ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration, with protein aggregation being a key pathological hallmark. Specifically, toxic dipeptide repeat proteins, such as aggregating glycine-alanine ((GA)n) peptides, are strongly implicated in disease progression, particularly in cases linked to C9orf72 hexanucleotide repeat expansions. Current treatments for ALS are limited, highlighting an urgent need for novel therapeutic strategies that directly address the underlying proteinopathy. Targeting these aggregates with engineered molecules represents a promising avenue to halt disease progression.

Researchers designed and synthesized novel polymer-peptide conjugates to target the aggregation of toxic dipeptide repeat proteins. The study focused on (GA)10 peptides, a specific glycine-alanine dipeptide repeat implicated in ALS. They evaluated the conjugates' ability to prevent aggregation when co-incubated with (GA)10 using optical density measurements to quantify aggregate formation. Additionally, the team assessed the conjugates' capacity to disperse pre-aggregated (GA)10 structures. Transmission electron microscopy was employed to visually confirm and characterize the presence and morphology of aggregates and their disruption.

The study demonstrated that the designed polymer-peptide conjugates effectively interfered with the aggregation process of (GA)10 dipeptide repeats.

Co-incubation of the polymer-peptide conjugates with (GA)10 peptides significantly prevented the formation of new aggregates, as evidenced by optical density measurements. Furthermore, the conjugates exhibited a crucial ability to act on existing pathological structures, successfully dispersing pre-aggregated (GA)10. Transmission electron microscopy provided visual confirmation of these effects, showing a clear reduction in aggregate presence and a disruption of their typical fibrillar morphology in the presence of the conjugates. These findings collectively indicate a dual mechanism of action: both preventing initial aggregation and actively breaking down existing aggregates, which is vital for targeting established pathology in ALS.