Protein aggregation underlies the basis for many degenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and inherited myopathies. In these diseases, a protein aggregates and then accumulates within selected cellular populations mediating cell death and disease. Why these aggregates accumulate is unclear however a failure in the proper folding and degradation of cellular protein has been postulated. Using next generation sequencing of small families with hereditary protein aggregate myopathies in the Washington University Neuromuscular Clinic, we identified mutations in the Hsp40 co-chaperone DNAJB6 as causative in limb girdle muscular dystrophy 1E. DNAJB6 is an abundant chaperone protein that interacts with aggregate proteins and facilitates their clearance in cell culture. We propose to use a multi-disciplinary approach to explore the function and dysfunction of DNAJB6 in protein aggregate disorders using yeast genetics, transgenic mouse models and human tissue.
“Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models”
R01 AR068797 (PIs, True-Krob & Weihl)
National Institute of Arthritis and Musculoskeletal and Skin Diseases
“Therapeutic modulation of chaperone function in LGMD1D”
Muscular Dystrophy Association Research Grant (PI, Weihl)
Stein KC, Bengoechea R, Harms MB, Weihl CC*, True HL*. Myopathy-causing mutations in an Hsp40 chaperone disrupt interactions with specific client conformers. Journal of Biological Chemistry. 289(30):21120-21130, (2014). *co-corresponding authors.
Bengoechea R, Pittman SK, Tuck EP, True HL, and Weihl CC*. Myofibrillar disruption and RNA binding protein aggregation in a mouse model of limb girdle muscular dystrophy 1D. Human Molecular Genetics. 24(23):6588-602, (2015). *corresponding author
Updated June 2017