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


Program Director

Randal J. Kaufman, Ph.D.

Secondary Appointments

Charles Spruck, Ph.D.


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

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome.

Hooshmandi M, Sharma V, Thörn Perez C, Sood R, Krimbacher K, Wong C, Lister KC, Ureña Guzmán A, Bartley TD, Rocha C, Maussion G, Nadler E, Roque PM, Gantois I, Popic J, Lévesque M, Kaufman RJ, Avoli M, Sanz E, Nader K, Hagerman RJ, Durcan TM, Costa-Mattioli M, Prager-Khoutorsky M, Lacaille JC, Martinez-Cerdeno V, Gibson JR, Huber KM, Sonenberg N, Gkogkas CG, Khoutorsky A

Neuron 2023 Jul 13 ;

HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.

Mawambo G, Oubaha M, Ichiyama Y, Blot G, Crespo-Garcia S, Dejda A, Binet F, Diaz-Marin R, Sawchyn C, Sergeev M, Juneau R, Kaufman RJ, Affar EB, Mallette FA, Wilson AM, Sapieha P

J Neuroinflammation 2023 Jun 21 ;20(1):145

mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes.

Hofmann C, Löwenthal Z, Aghajani M, Kaufman RJ, Katus HA, Frey N, Glembotski CC, Völkers M, Doroudgar S

Am J Physiol Heart Circ Physiol 2023 Aug 1 ;325(2):H311-H320

β(2)-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice.

Zhao Y, Zheng Q, Hong Y, Gao Y, Hu J, Lang M, Zhang H, Zhou Y, Luo H, Zhang X, Sun H, Yan XX, Huang TY, Wang YJ, Xu H, Liu C, Wang X

Nat Neurosci 2023 Jul ;26(7):1170-1184

Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.

Mastracci TL, Apte M, Amundadottir LT, Alvarsson A, Artandi S, Bellin MD, Bernal-Mizrachi E, Caicedo A, Campbell-Thompson M, Cruz-Monserrate Z, El Ouaamari A, Gaulton KJ, Geisz A, Goodarzi MO, Hara M, Hull-Meichle RL, Kleger A, Klein AP, Kopp JL, Kulkarni RN, Muzumdar MD, Naren AP, Oakes SA, Olesen SS, Phelps EA, Powers AC, Stabler CL, Tirkes T, Whitcomb DC, Yadav D, Yong J, Zaghloul NA, Pandol SJ, Sander M

Diabetes 2023 Apr 1 ;72(4):433-448

Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.

Hung HH, Nagatsuka Y, Soldà T, Kodali VK, Iwabuchi K, Kamiguchi H, Kano K, Matsuo I, Ikeda K, Kaufman RJ, Molinari M, Greimel P, Hirabayashi Y

Proc Natl Acad Sci U S A 2022 Dec 20 ;119(51):e2214957119

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