Transmissible intracellular protein aggregates contribute to the pathogenesis of neurodegenerative diseases. The transmitted aggregate corrupts soluble, unaggregated protein in the nave cell, spreading disease pathology from cell to cell. Whether cell to cell transmission of protein aggregate conformers applies to diseases other than neurodegeneration is not known but has critical implications for human health and disease pathogenesis. Our research program studies a large class of myodegenerative disorders that are due to the misfolding and aggregation of intracellular proteins. In fact many of the same proteins that cause neurodegeneration are found deposited in protein aggregate myopathies (PAMs) and include tau, ?-amyloid, ?-synuclein and TDP-43. One prototypical PAM also termed myofibrillar myopathy (MFM) is due to dominantly inherited mutations in the gene encoding the muscle specific intermediate filament desmin, DES. We hypothesize that similar to aggregates in neurodegeneration, desmin adopts distinct aggregate conformations that can be transmitted from cell to cell. These proteopathic desmin seeds corrupt normal desmin architecture within affected myofibers and spread throughout skeletal muscle fascicles leading to focal pathology and atrophy. This proposal will address three specific aims.
Aim 1 : Determine if recombinant desmin aggregates induce templated aggregate conversion of A) recombinant desmin in vitro and B) intracellular desmin monomer or filaments in skeletal muscle in vivo.
Aim 2 : Determine if desmin aggregates isolated from mouse skeletal muscle or human muscle biopsies can induce templated aggregate conversion of A) recombinant desmin in vitro and B) intracellular desmin monomer or filaments in skeletal muscle in vivo.
Aim 3 : Determine if desmin aggregates can transmit from cell to cell in myoblast cultures.
The spread of protein aggregate pathology in neurodegeneration is fundamental to disease pathogenesis. Several age associated muscle diseases have protein aggregate pathology. This proposal will evaluate aggregate spreading pathology in myodegenerative syndromes.
