Lawreen H. Connors
Associate Research Professor of Biochemistry
Department of Biochemistry
Boston University School of Medicine
Silvio Conte Building, K507
72 E. Concord Street
Boston, MA 02118
Phone: 617-638-4313
Fax: 617-638-5226
Email: lconnors@bu.edu
Education
B.S., Boston College, Chestnut Hill, MA
M.S., Tufts University, Medford, MA
Ph.D., Boston University, Boston, MA
Research Interest:
The systemic amyloid diseases are protein misfolding and deposition disorders that occur when one of several plasma circulating proteins adopts a non-native conformation that leads to aberrant self-association and aggregation of the protein. The aggregates form defined fibrillar structures which ultimately precipitate as amyloid deposits in the extracellular compartments of targeted tissues/organs. Pathological effects are thought to be related to the acute cellular toxicity of soluble prefibrillar aggregates, as well as the mechanical disruption of tissue function by the deposited amyloid fibrils.
One of the main areas of my research focuses on understanding the amyloidogenic nature of transthyretin (TTR), normally a soluble protein present in plasma and cerebral spinal fluid. Both wild-type and specific variant forms of TTR can be amyloidogenic, but disease onset is delayed in what appears to be an age-dependent mechanism. Our investigations are aimed at identifying specific age-related factors required to initiate the disease process; these factors likely include structural features that are both intrinsic and extrinsic to TTR. My research attempts to link protein biochemistry to disease pathology by studying the role of amino acid alterations, post-translational modifications (glycosylation, sulfonation, cysteinylation and phosphorylation) and metabolic processing in TTR amyloid fibril formation. We have precisely defined the molecular composition of numerous amyloidogenic TTR proteins derived from patient serum and tissue samples using mass spectrometry, anyalytical ultracentrifugation, and electron microscopy. In addition, using a proteomic approach, we have identified several tissue components present in patient specimens which may be effectors of amyloidogenesis. With recombinantly-generated proteins, we are studying the molecular stability of various forms of TTR, as well as the heteroassociations of TTR with these deposited molecular constituents using electrophoretic, chromatographic, and histological techniques. A translational component of our studies involves the study of a variety of compounds, including the small molecules diflunisal and tocopherol, as. potential inhibitors of TTR aggregation and fibril formation. Furthermore, since TTR-associated amyloid diseases often feature neuropathies, we are also studying the direct and indirect effects of amyloidogenic forms of TTR on cultured primary neuronal cells.
Representative Publications:
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.
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, 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 .
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.
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.
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.
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.
