Abstract
Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid. Desmin peptides corresponding to putative amyloidogenic regions formed seeding-competent amyloid fibrils. Amyloid formation was increased when disease-associated mutations were made within the peptide, and this conversion was inhibited by the anti-amyloid compound epigallocatechin-gallate. Moreover, a purified desmin fragment (aa 117 to 348) containing both amyloidogenic regions formed amyloid fibrils under physiologic conditions. Desmin fragment-derived amyloid coaggregated with full-length desmin and was able to template its conversion into fibrils in vitro. Desmin amyloids were cytotoxic to myotubes and disrupted their myofibril organization compared with desmin monomer or other nondesmin amyloids. Finally, desmin fragment amyloid persisted when introduced into mouse skeletal muscle. These data suggest that desmin forms seeding-competent amyloid that is toxic to myofibers. Moreover, small molecules known to interfere with amyloid formation and propagation may have therapeutic potential in MFM.
Highlights
Myofibrillar myopathies (MFMs) are a family of genetically defined degenerative myopathies that are due to mutations in 2 categories of proteins: Z-disk elements or protein chaperones [1]
Protein aggregation and the deposition of amyloid is a common feature in neurodegeneration, but can be seen in degenerative muscle diseases known as myofibrillar myopathies (MFMs)
We suggest that desmin amyloids are the culprit of myofiber degeneration and that they may share other amyloid properties, such as seeding, and may be important mediators of MFM pathogenesis
Summary
Myofibrillar myopathies (MFMs) are a family of genetically defined degenerative myopathies that are due to mutations in 2 categories of proteins: Z-disk elements or protein chaperones [1]. Disease mutations in sarcomeric structural proteins that reside at the Z-disk such as desmin, myotilin, filamin C, and Z-band alternatively spliced PDZ-motif lead to their accumulation and aggregation within myofibers. MFM patient muscle is unified by characteristic features that include muscle degeneration, protein inclusions, congophilic amyloid, and the aggregation of myofibrillar proteins such as desmin and myotilin [1, 2]. The present study demonstrates that similar to neurodegenerative proteins, desmin can form amyloid and template the amyloidogenic conversion of unaggregated desmin protein. This desmin-derived amyloid is toxic to myocytes and persists when introduced into skeletal muscle, in contrast to unaggregated desmin. These data demonstrate that desmin itself can form amyloid and expand the mechanism of proteinopathies to skeletal muscle
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