The Keck Autoimmune Disease Center
Faculty, Graduate Program
Molecular Basis of Acquired and Hereditary Human Disease
In the human amyloidoses, soluble proteins, synthesized and secreted from the cell, become insoluble in tissues with resultant organ compromise. The serum protein transthyretin is the precursor to the deposited protein in late-onset hereditary and acquired forms of neurologic, heart and kidney amyloidosis. We have established a disease model by creating a strain of mice carrying the human gene. In humans, amyloid deposition requires many years for initiation and progression. In our transgenic mice, by two years of age, a majority develop age-dependent deposition of the human protein in the heart and/or kidneys, a delay consistent with the late onset seen in humans. Prior to the appearance of Congophilic fibrils, the animals display less structured deposits that appear to be precursors to the amyloid fibrils. Analysis of this apparent in vivo folding intermediate should provide insight into the pathologic process responsible for the human disease. Our studies are designed to determine why deposition is age-dependent and what factors modulate the changes in protein conformation from the non-fibrillar to the fibrillar state.
M.D., Medicine, Tufts University, 1962
B.S., Union College, 1958
1980-1981, American Cancer Society Scholar in Cancer Research
1997-2000, Frank G. Spencer Fellow New York Affiliate American Heart Association
2000, Edward Bierman Lecturer Mid-Winter Conference on Controversies in Medicine;
1993-Present, Amyloid, The Journal of Protein Folding Disorders
1988-1991, Arthritis and Rheumatism
Teng MH, Yin J, Vidal R, Ghiso J, Tagoe C, Gallo G and Buxbaum JN: Amyloid and non-fibrillar tissue deposits in animals transgenic for wild type human transthyretin: A possible model for senile systemic amyloidosis. Laboratory Investigation 81:385-396, 2001.
Buxbaum JN. Diseases of protein conformation: what do in vitro experiments tell us about the in vivo diseases? Trends in Biochemical Sciences 28 (11):585-92, 2003.
Reixach N, Deechongkit S, Foss T, Jiang X, Kelly JW, Buxbaum JN. Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci (USA) 101(9):2817-2822, 2004.
Soares ML, Coelho T, Sousa A, Batalov S, Conceição I, Sales-Luís ML, Ritchie MD, Williams SM, Nievergelt CM, Schork NJ, Saraiva MJ, Buxbaum JN. Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single gene disease. Hum. Mol. Gen. 14(4):543-553, 2005.