Desmin Mutations Disrupt Filament Elongation and Drive Polymorphic Aggregation

R406W desmin forms unit-length filaments with wild-type-like kinetics but then progressively associates into fibrillar clusters and stops elongating, unlike wild-type continuous filament growth.

• Why it matters: Understanding when desmin assembly shifts from productive filament maturation to aggregation is key to explaining how dominant missense myopathy mutations generate intracellular protein aggregates.
• What they did: Wild-type desmin and N342D, L345P, R350P, and R406W were tested for assembly kinetics by dual-wavelength stopped-flow spectroscopy, supported by atomic force microscopy and molecular dynamics simulations.
• The result: Quantitative AFM plus kinetic modeling shows wild-type elongates continuously, R406W arrests elongation via cluster formation, while N342D, L345P, and R350P collapse into globular complexes that coalesce into larger aggregates.

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