Proteins are the workhorses of the cell, and their function depends on their shape.
When proteins are misfolded or damaged, their shape becomes flawed and they can’t perform their duties. Faulty proteins need to be eliminated before they accumulate, clump or become toxic. Although there are intrinsic cell mechanisms that recognize defective proteins and attempt to remove them, these systems go awry as we age. Almost every age-related degenerative disease is linked to protein misfolding.
Our focus is on understanding how cells discriminate between functional and nonfunctional proteins. We have made important discoveries about the damaging impact of oxidative stress on protein structure and function in the neurodegenerative diseases of Alzheimer’s and Parkinson’s, metabolic diseases of diabetes and liver failure, and inflammatory disease and cancer. Our findings will be translated into new therapies that improve protein folding and preserve cell function in diseases that are major worldwide health concerns.
– Randal J. Kaufman, Ph.D., Program Director
Oubaha M, Miloudi K, Dejda A, Guber V, Mawambo G, Germain MA, Bourdel G, Popovic N, Rezende FA, Kaufman RJ, Mallette FA, Sapieha P
Sci Transl Med 2016 Oct 26 ;8(362):362ra144
SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.
Huang TY, Zhao Y, Li X, Wang X, Tseng IC, Thompson R, Tu S, Willnow TE, Zhang YW, Xu H
J Neurosci 2016 Jul 27 ;36(30):7996-8011
Wang C, Niu M, Zhou Z, Zheng X, Zhang L, Tian Y, Yu X, Bu G, Xu H, Ma Q, Zhang YW
Neurobiol Aging 2016 Oct ;46:22-31
Soluble SORLA enhances neurite outgrowth and regeneration through activation of the EGF Receptor/ERK signaling axis.
Stupack J, Xiong XP, Jiang LL, Zhang T, Zhou L, Campos A, Ranscht B, Mobley W, Pasquale EB, Xu H, Huang TY
J Neurosci 2020 Jun 29 ;
Hetz C, Zhang K, Kaufman RJ
Nat Rev Mol Cell Biol 2020 May 26 ;
Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role For Peroxiredoxin 4 in Proinsulin Folding.
Tran DT, Pottekat A, Mir SA, Loguercio S, Jang I, Campos AR, Scully KM, Lahmy R, Liu M, Arvan P, Balch WE, Kaufman RJ, Itkin-Ansari P
Diabetes 2020 May 26 ;
Role of Proinsulin Self-Association in Mutant <i>INS</i> Gene-Induced Diabetes of Youth.
Sun J, Xiong Y, Li X, Haataja L, Chen W, Mir SA, Lv L, Madley R, Larkin D, Anjum A, Dhayalan B, Rege N, Wickramasinghe NP, Weiss MA, Itkin-Ansari P, Kaufman RJ, Ostrov DA, Arvan P, Liu M
Diabetes 2020 May ;69(5):954-964
Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum.
Poothong J, Pottekat A, Siirin M, Campos AR, Paton AW, Paton JC, Lagunas-Acosta J, Chen Z, Swift M, Volkmann N, Hanein D, Yong J, Kaufman RJ
Blood 2020 May 21 ;135(21):1899-1911
The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts.
Stauffer WT, Blackwood EA, Azizi K, Kaufman RJ, Glembotski CC
Int J Mol Sci 2020 Feb 18 ;21(4)