Degenerative Diseases Program

Differentiation of Neural Stem Cells

Faulty proteins

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.

Director's statement

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

Appointments

Program Director

Randal J. Kaufman, Ph.D.

Primary Appointments

Jerold Chun, M.D., Ph.D.
Shengjie Feng, Ph.D.
Timothy Huang, Ph.D
Xiao Tian, Ph.D.

Secondary Appointments

Charles Spruck, Ph.D.

Publications

Chop/Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice.

Yong J, Parekh VS, Reilly SM, Nayak J, Chen Z, Lebeaupin C, Jang I, Zhang J, Prakash TP, Sun H, Murray S, Guo S, Ayala JE, Satin LS, Saltiel AR, Kaufman RJ

Sci Transl Med 2021 Jul 28 ;13(604)

Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.

Zhu B, Liu Y, Hwang S, Archuleta K, Huang H, Campos A, Murad R, Piña-Crespo J, Xu H, Huang TY

Mol Neurodegener 2022 Sep 2 ;17(1):58

Somatic APP gene recombination in Alzheimer's disease and normal neurons.

Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, Chun J

Nature 2018 Nov ;563(7733):639-645

P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Zhang D, Zhang W, Ming C, Gao X, Yuan H, Lin X, Mao X, Wang C, Guo X, Du Y, Shao L, Yang R, Lin Z, Wu X, Huang TY, Wang Z, Zhang YW, Xu H, Zhao Y

Neuron 2024 Mar 12 ;

Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.

Arunagiri A, Alam M, Haataja L, Draz H, Alasad B, Samy P, Sadique N, Tong Y, Cai Y, Shakeri H, Fantuzzi F, Ibrahim H, Jang I, Sidarala V, Soleimanpour SA, Satin LS, Otonkoski T, Cnop M, Itkin-Ansari P, Kaufman RJ, Liu M, Arvan P

Protein Sci 2024 Apr ;33(4):e4949

ATF6 protects against protein misfolding during cardiac hypertrophy.

Hofmann C, Aghajani M, Alcock CD, Blackwood EA, Sandmann C, Herzog N, Groß J, Plate L, Wiseman RL, Kaufman RJ, Katus HA, Jakobi T, Völkers M, Glembotski CC, Doroudgar S

J Mol Cell Cardiol 2024 Apr ;189:12-24

Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion.

Chen Z, Wang S, Pottekat A, Duffey A, Jang I, Chang BH, Cho J, Finck BN, Davidson NO, Kaufman RJ

Mol Metab 2024 Feb ;80:101874

Author Correction: Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Victorelli S, Salmonowicz H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, Hall-Younger E, Machado Espindola-Netto J, Jurk D, Lagnado AB, Sales Gomez L, Farr JN, Saul D, Reed R, Kelly G, Eppard M, Greaves LC, Dou Z, Pirius N, Szczepanowska K, Porritt RA, Huang H, Huang TY, Mann DA, Masuda CA, Khosla S, Dai H, Kaufmann SH, Zacharioudakis E, Gavathiotis E, LeBrasseur NK, Lei X, Sainz AG, Korolchuk VI, Adams PD, Shadel GS, Tait SWG, Passos JF

Nature 2024 Jan ;625(7995):E15

Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells.

Amiri M, Kiniry SJ, Possemato AP, Mahmood N, Basiri T, Dufour CR, Tabatabaei N, Deng Q, Bellucci MA, Harwalkar K, Stokes MP, Giguère V, Kaufman RJ, Yamanaka Y, Baranov PV, Tahmasebi S, Sonenberg N

Cell Rep 2024 Jan 23 ;43(1):113615

Show All Publications