Coronavirus COVID-19 Information
- Information for patients who have a scheduled test or appointment
- Information for hospital visitors
- Donations: How you can help
Inclusion body myositis, the most common muscle disease associated with aging, has recently been linked to the formation of protein aggregates, but the mechanism of toxicity is currently unknown. Among the proteins found in these aggregates are RNA-binding proteins that form intracellular inclusions in several neurodegenerative diseases. Although the role of these aggregation-prone proteins is unclear, it has recently been established that missense mutation at a conserved position in two RNA-binding proteins, heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1 and hnRNPA1, causes hereditary forms of a related condition, inclusion body myopathy (IBM), as part of multisystem proteinopathy (MSP).
The clinical and pathological similarity of the genetic and sporadic diseases suggests a common cause mediated by aggregation-prone RNA-binding proteins. Although the toxicity of hnRNP aggregates and the connection between the formation of hnRNP aggregates and muscle disease has been demonstrated in animal models, the aggregation process and the mechanisms preventing aggregation under normal conditions are not yet clear.
The purpose of the pilot project is to demonstrate that high-resolution structural details of hnRNP aggregation could transform the potential to develop treatments for IBM. To this end, this project will test the hypotheses that the aggregation prone prion-like domain of hnRNPA2 is unstructured and that disease-associated mutations in the prion-like region encourage aggregation via glutamine, asparagine and tyrosine residues in the vicinity of the mutation. Determining the molecular details of hnRNP aggregation is a critical enabling step in the design of therapies to block the formation of aggregates and prevent disease, for example the design of aggregate assays to screen potential therapeutics.
The aggregation of RNA-binding proteins has been definitively linked to IBM, a disease with no effective therapies and no cure. The recent identification of dominant mutations that cause IBM pathology is highly important to identifying the underlying cause of the disease. Furthermore, prion-like domains are currently the focus of attention in many neurodegenerative diseases. Characterizing these aggregates puts the results of this work on the cutting edge of structural biology and will provide critical information for future therapies.