Gareth Morgan, Ph.D.
Title: Research Assistant Professor of Medicine
Research Interests: Amyloidosis; Protein Folding and Aggregation; Plasma Cell Disorders
My research group works on systemic amyloidosis, a group of rare diseases that are caused by the aggregation of proteins throughout the body. These diseases are deadly if untreated and often diagnosed late, so there is an urgent need to identify the molecular mechanisms involved and to develop new therapies. The Amyloidosis Center at BUSM and BMC is a national referral center for amyloidosis, where specialist physicians deliver world-leading care and run clinical trials to evaluate new treatments. In parallel, the Center carries out basic and translational research focused on identifying the molecular mechanisms of amyloidosis and addressing the needs of patients. My main area of research is to develop new strategies for the treatment of AL amyloidosis, a relatively common form of amyloidosis caused by aggregation of antibody light chain proteins. We use biophysical techniques to measure the folding and aggregation of these light chains. Our work suggests that stabilization of light chains by small molecules could prevent aggregation and therefore prevent disease progression. In AL amyloidosis, light chains are secreted by clonally expanded plasma cells, a condition known as monoclonal gammopathy, which is related to a more aggressive cancer, multiple myeloma. Recent developments in therapy for myeloma have dramatically improved the survival of patients, and have been successfully adapted for use in AL amyloidosis. We are working to apply approaches used in myeloma to AL amyloidosis, aiming to develop diagnostic tools and strategies that could improve patients’ survival and quality of life.
1.Morgan GJ, Kelly JW. The Kinetic Stability of a Full-Length Antibody Light Chain Dimer Determines whether Endoproteolysis Can Release Amyloidogenic Variable Domains. J Mol Biol. 2016 10 23; 428(21):4280-4297. PMID: 27569045; DOI: 10.1016/j.jmb.2016.08.021
2. Morgan GJ, Usher GA, Kelly JW. Incomplete Refolding of Antibody Light Chains to Non-Native, Protease-Sensitive Conformations Leads to Aggregation: A Mechanism of Amyloidogenesis in Patients? Biochemistry. 2017 Dec 19; 56(50):6597-6614. PMID: 29200282; DOI: 10.1021/acs.biochem.7b00579
3. Cooley CB, Ryno LM, Plate L, Morgan GJ, Hulleman JD, Kelly JW, Wiseman RL. Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proc Natl Acad Sci U S A. 2014 Sep 09; 111(36):13046-51. PMID: 25157167; DOI: 10.1073/pnas.1406050111
4. Foit L, Morgan GJ, Kern MJ, Steimer LR, von Hacht AA, Titchmarsh J, Warriner SL, Radford SE, Bardwell JC. Optimizing protein stability in vivo. Mol Cell. 2009 Dec 11; 36(5):861-71. PMID: 20005848; DOI: 10.1016/j.molcel.2009.11.022
5. Morgan GJ, Giannini S, Hounslow AM, Craven CJ, Zerovnik E, Turk V, Waltho JP, Staniforth RA. Exclusion of the native alpha-helix from the amyloid fibrils of a mixed alpha/beta protein. J Mol Biol. 2008 Jan 11; 375(2):487-98. PMID: 18021806; DOI: 10.1016/j.jmb.2007.10.033