Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers

Area of Science:

• Muscle biology
• Protein misfolding diseases
• Neurodegenerative disease research

Background:

• Desmin-associated myofibrillar myopathy (MFM) shares pathological similarities with protein aggregate diseases linked to neurodegeneration.
• Desmin, a muscle-specific intermediate filament, aggregates in MFM patients due to disease mutations.

Purpose of the Study:

• To investigate whether desmin can form amyloid fibrils, similar to proteins implicated in neurodegeneration.
• To explore the potential therapeutic implications of targeting desmin amyloid formation in MFM.

Main Methods:

• Synthesized desmin peptides corresponding to putative amyloidogenic regions.
• Induced amyloid formation in desmin peptides and a purified desmin fragment (aa 117-348).
• Assessed the impact of disease-associated mutations and epigallocatechin-gallate on desmin amyloid formation.
• Evaluated the cytotoxicity and myofibril organization disruption caused by desmin amyloids in myotubes.
• Examined the persistence of desmin fragment amyloid in mouse skeletal muscle.

Main Results:

• Desmin peptides formed seeding-competent amyloid fibrils, with increased formation in disease-associated mutants.
• A purified desmin fragment formed amyloid fibrils under physiological conditions, coaggregated with full-length desmin, and templated its conversion.
• Desmin amyloids exhibited cytotoxicity to myotubes, disrupting myofibril organization.
• Desmin fragment amyloid persisted in mouse skeletal muscle.
• Epigallocatechin-gallate inhibited desmin amyloid formation.

Conclusions:

• Desmin forms seeding-competent, toxic amyloid fibrils that contribute to myofiber pathology in MFM.
• Targeting desmin amyloid formation and propagation with small molecules may offer a therapeutic strategy for MFM.