Hetz Lab

Claudio Hetz, PhD

Professor in Residence

ER proteostasis in brain aging and disease

Lab focus

Aging is the main risk factor to develop neurodegenerative diseases. Alteration in the buffering capacity of the proteostasis network is proposed as one of the triggering steps leading to abnormal protein aggregation, which is also a central hallmarks of brain aging.  The endoplasmic reticulum (ER) is a major node of the proteostasis network altered in brain diseases and during aging. ER stress triggers a signaling reaction known as the unfolded protein response (UPR), which aims restoring proteostasis through the induction of adaptive programs or the activation of cell death programs when damage is chronic and cannot be repaired

The Hetz lab studies the understanding the molecular basis of perturbations of subcellular organelle function, their relationship to pathological conditions affecting the nervous system, aging and the development of prototypic therapies to prevent this damage. We utilize mice and cell culture to study of stress signals linked with aging and age-related neurodegenerative diseases. We have performed several studies in models of Huntington´s disease, spinal cord injury, prion related disorders, ALS among other diseases to test the biomedical potential of the UPR as a possible disease target.

 

Why it matters

We believe the significance of the UPR to brain aging and its contribution to disease. Currently we developing a systematic strategy to define the consequences of targeting specific UPR components in neurodegenerative diseases, in addition to address the physiological significance of the pathway to brain function and aging. One of our major areas of biotechnological development is gene therapy.

Our idea is to find factors that dictate the natural brain aging, to avoid the emergence of pathological aging and increase cognitive healthspan.

Claudio Hetz, PhD

The Hetz lab is pleased to acknowledge the generous support of the following major funders:

Claudio Hetz was originally trained as Biotechnology Engineer at the University of Chile and performed his Ph. thesis in Biomedical Sciences at Serono Pharmaceutical Research Institute, Switzerland. This work was performed in the laboratory of Dr. Claudio Soto, and contributed to define the role of ER stress in Prion-related disorders. Then he did a postdoctoral training at Harvard University to study stress responses at the level of proteostasis control and its relation to disease. This work was supervised by Drs Stanley Korsmeyer and Laurie Glimcher, worl lider in apoptosis and ER stress research. He joined the University of Chile during 2007 and is currently Full Professor at Faculty of Medicine, in addition to hold and adjunct Professor position at the Buck Institute for Research in Aging in California and a visiting professor position at Harvard. He is also currently the Director of the Biomedical Neuroscience Institute (BNI) and associate investigator of the Center for Geroscience, Brain health and Metabolism (GERO).

His research focused on understanding the molecular basis of protein folding stress, its relationship to pathological conditions affecting the nervous system including ALS, Parkinson´s disease, and Alzheimer’s disease and the development of prototypic strategies to prevent neuronal damage. One of his major areas of biotechnological development is gene therapy. This group is one of the most productive laboratories in Chile and Latin America and is currently supported by various national and international organizations. He has received important award including the KIA International Award, FEBS Anniversary Prize, TWAS-ROLAC and UNESCO Young Scientist Prize as outstanding young scientist in Latin America, the Santander Award, he was finalist in the Eppendorf and Science Award in Neurobiology, and was awarded with the Cell Biology Society and Bios-Chile prize as the best young scientist of Chile. Dr. Hetz H-factor is 55, publishing more than 200 papers with more than 18,000 citations.

Hetz lab website or www.bni.cl; www.gerochile.org
Twitter: HetzLab; Youtube: Hetz Lab

Claudia Sepúlveda-Quiñenao M.Sc.
Labmanager-hetzlab@bni.cl
Phone: +562229786876
Selected Publications
  • Dufey E., Bravo-San Pedro JM., Eggers C., González-Quiroz M., Urra H., Sagredo A., Sepulveda D., Pihan P., Carreras-Sureda A., Hazari Y., Sagredo E., Gutierrez D., Valls C., Papaioannou A., Acosta-Alvear D., Campos G., Domingos PM., Pedeux R., Chevet E., Alvarez A., Godoy P., Walter P., Glavic A., Kroemer G., Hetz C. (2020).  Genotoxic stress triggers the activation of IRE1a-dependent RNA decay to modulate the DNA damage response. Nature Communications. 11(1):2401.
  • Hetz C, Zhang K., Kaufman R. (2020). Mechanisms, regulation and functions of the unfolded protein response. Nature Reviews Mol. Cell. Biol. 10.1038/s41580-020-0250-z.
  • Carreras-Sureda A., Jaña F., Urra H., Durand S., Mortenson D., Sagredo A., Bustos G., Hazari Y., Ramos-Fernández E., Sassano ML., Pihan P., van Vliet A., Gonzalez-Quiroz M., Tores A., Tapia-Rojas C., Kerkhofs M., Vicente R., Kaufman R., Inestrosa N., Gonzalez C., Wiseman R., Agostinis P., Bultynck G., Court F., Kroemer G., Cárdenes JC.,  and Hetz C. (2019). Non-canonical role of IRE1 as a functional determinant of mitochondria-associated endoplasmatic reticulum composition to control calcium transfer and bioenergetics.  Nature Cell Biology. 21(6):755-767.
  • Oñate M., Catenaccio A., Salvadores N.,Saquel C., Martinez A.,  Moreno-Gonzalez I.,  Gamez N., Soto P., Soto C., Hetz C.* and Court F. (2019). The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease. Cell Death Diff. 10.1038/s41418-019-0408-4.
  • Gerakis Y., Quintero M., Li H.  and Hetz C. (2019). The UFMylation system in proteostasis ans beyond. Trends in Cell biology. 29(12):974-986.
  • Gonzalez-Teuber V., Albert-Gasco H., Auyeung V., Papa F., Mallucci G., and Hetz C. (2019). Small molecules to improve ER Proteostasis in disease.  Trends Pharmacol Sci. 40(9): 684-695.
  • Hetz C., and Axten J. (2019).  Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol. 15:764-775.
  • Medinas D., Cabral-Miranda F., and Hetz C. (2019). ER stress links aging to sporadic ALS. Aging. 11; 5-6.
  • Urra H., Henriquez D., Cánovas J., Villarroel-Campos D., Carreras-Sureda A., Pulgar E., Molina E., Hazari Y., Limia D., Alvarez-Rojas S., Figueroa R., Vidal R., Rodriguez D., Rivera C., Court F., Couve A., Qui L., Chevet E., Akai R., Iwawaki T., Concha M., Glavic A., Gonzalez-Billault C., and Hetz C. (2018). IRE1 governs cytoskeleton remodeling and cell migration through a direct interaction with Filamin A. Nature Cell Biology. 20:942-953 
  • Medinas D., Rozas P., Martinez F., Woehlbier U., Brown RH., Bosco D., and Hetz C. (2018). Endoplasmatic reticulum stress leads to accumulation of wild-type SOD1 aggreegates associated with sporadic amyotrophic lateral sclerosis. Proc. Natl. Acad. Asci USA. 115:8209-8214 pii: 201801109.
  • Sepulveda D., Rojas-Rivera D., Rodriguez D., Groenendyk J., Köhler A., Lebeaupin C., Ito S., Urra H., Carreras-Sureda A., Vasseur-Cognet M., Chevet E., Campos G., Godoy P., Vaisar T., Bailly-Maitre B., Nagata K., Michalak M., Sierralta J., and Hetz C. (2018). Interactome screening identifies a novel function of the collagen chaperon Hsp47 as an adjustor of the unfolded protein response (UPR) transducer IRE1. Mol Cell. 69:238-252.
  • Matamala JM., Arias-Carrasco R., Sanchez C., Uhrig M., Bargsted L., Matus S., Maracaja-Coutinho V., Abarzua S., van Zundert B., Verdugo R., Manque P., Hetz C. (2018). Genome-wide circulating microRNA expression profiling reveals potential biomarkers for amyotrophic lateral sclerosis. Neurobiol. Aging. 64:123-138.
  • Mercado G., Castillo V., Soto P., López N., Axten J., Sardi P., Hoozemans J. and Hetz C.  (2018). Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease. Neurobiol. Dis. 112:136-148.
  • Hetz C. and Papa F. (2018). The unfolded protein response and cell fate control. Molecular Cell. 69:169-181.
  • Martínez G., Khatiwada S., Costa-Mattioli M., and Hetz C. (2018). ER proteostasis control of neuronal physiology and synaptic dysfunction. Trends Neurosci.  41(9):610-624. *#
  • Gerakis Y. and Hetz C. (2018). Emerging roles of ER stress in the aetiology and pathogenesis of Alzheimer’s disease. FEBS J. 63: 162-164.

Dr. Kapahi’s full publication list

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