Protein degradation pathways and their relation to aging, muscle weakness, and neurodegeneration

Inclusion body myopathies are a group of disabling skeletal muscle disorders. The most common form, inclusion body myositis (IBM), affects patients over the age of 50. There is no effective treatment. IBM muscle tissue contains characteristic “rimmed vacuoles” and eosinophilic cytoplasmic aggregates. These structures contain ubiquitin, ß-amyloid, apolipoprotein E, and phosphorylated tau, the same pathologic proteins present in Alzheimers Disease (AD) brains.

Mutations in the protein p97, also known as VCP (valosin containing protein), cause a dominantly inherited syndrome with an IBM phenotype. The pathologic consequence of these mutations has not been studied. p97/VCP belongs to the AAA ATPase (ATPases associated with other cellular activities) protein family and is implicated protein degradation via the ubiquitin-proteasome pathway.

My research uses both cellular and animal models of hereditary IBM to explore the underlying pathogenesis of this disease. These models allow us to understand mechanisms of protein misfolding and degradation in skeletal muscle and its relation to other inherited myopathies, muscular dystrophies, cachexia and normal aging.