Lawreen H. Connors
Boston University School of Medicine
Silvio Conte Building, Office: K507; Lab: K508
72 E. Concord Street
Boston, MA 02118
Lab Phone: 617-638-4348
B.S., Chemistry, Mathematics, Boston College, Chestnut Hill, MA
M.S., Chemistry, Tufts University, Medford, MA
Ph.D., Biochemistry, Boston University, Boston, MA
The systemic amyloid diseases are protein misfolding and deposition disorders. These pathologies feature the destabilization of one of several plasma proteins; the amyloidogenic protein adopts a non-native conformation that leads to aberrant self-association and aggregation. The aggregates form defined fibrillar structures which ultimately precipitate as amyloid deposits in the extracellular compartments of targeted tissues/organs. In addition to the mechanical disruption of tissue function by the deposited amyloid fibrils, pathological effects are thought to be related to the acute cellular toxicity of soluble prefibrillar amyloid aggregates. We are studying the amyloidogenic nature of transthyretin (TTR), normally a soluble protein present in plasma and cerebral spinal fluid. Both wild-type and variant forms of TTR can form amyloid deposits, but disease onset is delayed in what appears to be an age-dependent mechanism. Our investigations are aimed at identifying specific factors required to initiate the disease process; these factors likely include structural features that are both intrinsic and extrinsic to TTR. Specific areas of interest include the roles of amino acid alterations, post-translational modifications (glycosylation, sulfonation, cysteinylation) and heteroassociations in TTR amyloid fibril formation. We have extensively characterized TTR proteins derived from clinical specimens and identified proteomic differences in patient vs. age-matched control serum and tissue samples. TTR structural modifications and heteroassociations identified in the clinical samples are studied in vitro with recombinantly-generated proteins and several compounds, including diflunisal and α-tocopherol, are being investigated as potential inhibitors of TTR aggregation and fibril formation. Furthermore, since TTR-associated amyloid diseases often feature cardiomyopathy, we are also studying the effects of amyloidogenic forms of TTR on cultured primary cardiac cells.
- Tam M, Seldin DC, Forbes BM, Connors LH, Skinner M, Oran B, Quillen K, and Sanchorawala V: Spontaneous rupture of the liver in a patient with systemic AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation: a case report with literature review. Amyloid:Journal of Protein Folding Disorders, In Press, 2009.
- Bodi K, Prokaeva T, Spencer B, Eberhard M, Connors LH, and Seldin DC: AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences. Amyloid:Journal of Protein Folding Disorders 16(1):1-8, 2009.
- Biolo A, Ramamurthy S, Connors LH, O’Hara CJ, Meier-Ewert HK, Soo Hoo P, Sawyer DB, Seldin DC, and Sam F: Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail 1:249-257, 2009.
- Buxbaum J, Koziol J, and Connors LH: Serum transthyretin levels in senile systemic amyloidosis: effects of age, gender and ethnicity. Amyloid:Journal of Protein Folding Disorders 15(4):255-261, 2008.
- Kingsbury JS, Laue TM, Théberge R, Costello CE, and Connors LH: The modulation of transthyretin tetramer stability by cysteine-10 mixed disulfides and diflunisal:direct analysis by fluorescence-detected analytical ultracentrifugation. J Biol Chem 283(18), 11887–11896, 2008.
- Lavatelli F, Perlman DH, Spencer B, Prokaeva T, McComb ME, Théberge R, Connors LH, Bellotti V, Seldin DC, Merlini G, Skinner M, and Costello CE: Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Molecular and Cellular Proteomics 7(8):1570-83, 2008 .
- Connors LH, Jaing Y, Budnick M, Théberge R, Prokaeva T, Bodi KL, Seldin DC, Costello CE, and Skinner M: Heterogeneity in primary structure, post-translational modifications, and germline gene usage of nine full-length amyloidogenic kappa 1 immunoglobulin light chains. Biochemistry, 46:14259-14271, 2007.
- Prokaeva T, Spencer B, Kaut M, Ozonoff A, Doros G, Connors LH, Skinner M, and Seldin DC: Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features and survival. Arthritis Rheum 56(11):3858-68, 2007.
- Kingsbury JS, Klimtchuk ES, Théberge R, Costello CE, and Connors LH: Expression, purification, and in vitro cysteine-10 modification of native sequence recombinant human transthyretin. Prot Expr Purif 53(2):370-7, 2007.
- Kingsbury JS, Théberge R, Karbassi JA, Lim A, Costello CE, and Connors LH: Detailed structural analysis of amyloidogenic wild type transthyretin using a novel purification strategy and mass spectrometric techniques. Anal Chem 79(5):1990-8, 2007.
- Rosenzweig M, Skinner M, Prokaeva T, Théberge R, Costello CE, Drachman BM, and Connors LH: A new transthyretin variant (Glu61Gly) associated with cardiomyopathy. Amyloid:Journal of Protein Folding Disorders 14(1): 65-71, 2007.
- Kos CA, Ward JE, Malek K, Sanchorawala V, Wright DG, O’Hara C, Connors LH, Skinner M, and Seldin DC: Association of acquired von Willebrand syndrome with AL amyloidosis. Am J Hematol 82(5):363-7, 2007.
- Monis GF, Schultz C, Ren R, Eberhard J, Costello C, Connors L, Skinner M, and Trinkaus-Randall V: Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts. Am J Pathology 169:1939-52, 2006.
- Akar H, Seldin DC, Magnani B, O’Hara C, Berk JL, Schoonmaker C, Cabral H, Dember LM, Sanchorawala V, Connors LH, Falk RH, and Skinner M: Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis. Amyloid:Journal of Protein Folding Disorders 12:210-5, 2005.
- Ng B, Connors LH, Davidoff R, Skinner M, and Falk RH: Senile systemic amyloidosis presenting with heart failure: a comparison with light-chain associated (AL) amyloidosis. Arch Int Med 165:1425-9, 2005.
- Chung CM, Chiu JD, Connors LH, Gursky O, Lim A, Dykstra AB, Liepnieks J, Benson MD, Costello CE, Skinner M, and Walsh MT: Thermodynamic stability of a kappa I immunoglobulin light chain: relevance to multiple myeloma. Biophysical J 88:4232-42, 2005.
- Trinkaus-Randall V, Walsh MT, Steeves S, Monis G, Connors LH, and Skinner M: Cellular response of cardiac fibroblasts to amyloidogenic light chains. Am J Pathology 166:197-208, 2005
- Connors LH, Yamashita T, Yazaki M, Skinner M, and Benson MD: A rare transthyretin mutation (Asp18Glu) associated with cardiomyopathy. Amyloid:Journal of Protein Folding Disorders 11:61-6, 2004.
- Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, and Liao R: Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 94:1008-10, 2004.
- Connors LH, Lim A, Prokaeva T, Roskens VA, and Costello CE: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid:Journal of Protein Folding Disorders 10:160-84, 2003.