Biology of Neurodegeneration

PROFILE

In response to diverse stress stimuli, including nutrient restriction, infections or proteotoxicity, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2a) by one of four members of the eIF2a kinase family, which leads to a decrease in global protein synthesis and also the induction of selected genes that together promote cellular recovery. We are focused on understanding the contribution of this signaling pathway to neurodegenerative process and aging. Using in vivo and in vitro models, we study the consequences of targeting ISR components to open new therapeutic strategies for treating neurodegenerative diseases.

LAB MEMBERS

Research Head: Soledad Matus Montero.
Doctoral students: Luis Osorio
Research Assistants: Natalia Muñoz and Carolina Jerez.

COLLABORATIONS

National Collaborations:
• Dr. Rodrigo Pacheco (Fundación Ciencia & Vida). We are analyzing the role of the dopaminergic regulation of CD4+ T-cells in the development of amyotrophic lateral sclerosis.
• Dr. Christian González (Faculty of Science, Universidad de Chile). We are studying the role of the Kinase GCN2 in neural development.
• Dr. Patricio Olguín (Faculty of Medicine, Universidad de Chile). We are analyzing the contribution of the kinase GCN2 the development of amyotrophic lateral sclerosis.
• Dr. Claudio Hetz (Faculty of Medicine, Universidad de Chile). We are analyzing the contribution of the integrated stress response the development of amyotrophic lateral sclerosis.
• Dr. Luis Michea (Faculty of Medicine, Universidad de Chile). We are studying how dendritic cells and neutrophils contribute to the development and progression of hypertension.

International Collaborations:
• Dr. Brian Popko (Department of Neurology, University of Chicago). We are studying the role of the UPR sensor PERK in the progression of ALS.
• Dr. Peter Walter (UCSF). We are studying the therapeutic potential of molecules that inhibit the integrated stress response.
• Dr. Lionel Miller Igaz (IFIBIO-Houssay. UBA, Argentina).

SELECTED PUBLICATIONS

  • Garcia-Huerta P., Bargsted L., Rivas A., Matus S., Vidal R. “ER chaperones in neurodegenerative disease: Folding and beyond”. Brain Res. (2016) Oct 1; 1648(Pt B):580-587 | | ABSTRACT
  • Bargsted L., Hetz C., Matus S. “ERp57 in neurodegeneration and regeneration”. Neural Regen Res. (2016) Feb;11(2):232-3. | | ABSTRACT
  • Klionsky D.J., et al. “Guidelines for the use and interpretation of assays for monitoring autophagy” 3rd (edition). Autophagy. 2016;12(1):1-222. | | ABSTRACT
  • Woehlbier U., Colombo A., Saaranen M.J., Pérez V., Ojeda J., Bustos F.J., Andreu C.I,. Torres M., Valenzuela V., Medinas D.B., Rozas P., Vidal R.L., Lopez-Gonzalez R., Salameh J., Fernandez-Collemann S., Muñoz N., Matus S., Armisen R., Sagredo A., Palma K., Irrazabal T., Almeida S., Gonzalez-Perez P., Campero M., Gao F.B., Henny P., van Zundert B., Ruddock L.W., Concha M.L. Henriquez J.P., Brown R.H., Hetz C. “ALS-linked protein disulfide isomerase variants cause motor dysfunction”. (2015). EMBO J. 2016 Apr 15;35(8):845-65. | | ABSTRACT
  • Torres M., Medinas D.B., Matamala J.M., Woehlbier U., Cornejo V.H., Solda T., Andreu C., Rozas P, Matus S, Muñoz N., Vergara C., Cartier L., Soto C., Molinari M., Hetz C. “The Protein Disulfide Isomerase ERp57 Regulates the Steady-State Levels of the Prion Protein.” (2015). J Biol Chem. 2015 290 (39) :23631-45. | | ABSTRACT
  • Vidal R., Matus S., Bargsted L. and Hetz C. (2014). “Targeting Autophagy in Neurodegenerative Diseases" TiPS, 2014. 35. 11: p583–591. | | ABSTRACT
  • Matus S, Bosco DA, Hetz C. 2014 “Autophagy meets fused in sarcoma-positive stress granules”. Neurobiology of Aging. 2014 12: 2832-5. | | ABSTRACT
  • Matus S. Medina D and Hetz C. (2014) “Common Ground: Stem Cell Approaches Find Shared Pathways Underlying ALS”. Cell Stem Cell. 2014. 14: 697-699. | | ABSTRACT
  • Nassif M., Valenzuela V., Rojas-Rivera D., Vidal R., Matus S., Castillo K., Fuentealba Y., Kroemer G., Levine B. and Hetz C. (2014) "Pathogenic role of Beclin 1/BECN1 in the development of amyotrophic lateral sclerosis" Autophagy. 2014 10:7,1-16. | | ABSTRACT
  • Matus S., Valenzuela V., Hetz, C. (2014). “A new method to measure of autophagy flux in the nervous system”. Autophagy. 2014 10(4):710-714. | | ABSTRACT
  • Matus S., Valenzuela V, Medinas D, Hetz, C. (2013). “New insights about the role of ER stress in ALS”. Int J Cell Biol. 2013:674751. Review. | | ABSTRACT
  • Matus S, Lopez E, Valenzuela V, Nassif M and Hetz C. (2013). “Functional role of the transcription factor ATF4 in the pathogenesis of amyotrophic lateral sclerosis”. PLoS One. 2013 Jul 18;8(7):e66672. | | ABSTRACT
  • Castillo K, Valenzuela V, Nassif M, Oñate M, Encina G, Matus S, Irrazabal T, Parsons G, Court F, Schneider B, Aebischer P, Armentano D and Hetz C. (2013). “Measurement of autophagy flux in the nervous system in vivo”. Cell Death and Differentiation. 2013; 4:e917. | | ABSTRACT
  • Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court F, van Zundert B, and Hetz C. (2013). "Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons". Autophagy. 2013 Jun 6;9(9). | | ABSTRACT
  • Matus S, Castillo K, Hetz C. (2012). “Hormesis: protecting neurons against cellular stress in Parkinson disease”. Autophagy. Jun;8(6):997-1001. | | ABSTRACT
  • Gupta S, Read DE, Deepti A, Cawley K, Gupta A, Oommen D, Verfaillie T, Matus S, Smith MA, Mott JL, Agostinis P, Hetz C, Samali A. (2012). “Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis”. Cell Death Dis. 2012 Jun 28;3:e333. | | ABSTRACT
  • Matus S., Glimcher LH., and Hetz C. (2011). “Protein folding stress in neurodegenerative diseases: a glimpse into the ER”. Curr Op. Cell Biol. 23:239-52. | | ABSTRACT
  • Nassif M, Matus S, Castillo K, and Hetz C. (2010). “Amyotrophic lateral sclerosis pathogenesis: a journey through the secretory pathway”. Antiox Red. Sig, 13:1955-89. | | ABSTRACT
  • Matus S., Nassif M., Glimcher LH, and Hetz C. (2009). “XBP-1 deficiency in the nervous system revealed a homeostatic switch to activate autophagy”. Autophagy. Nov 6;5(8). (Cover illustration). | | ABSTRACT
  • Hetz C, Thielen P, Matus S., M Nassif, Court F., Cuervo AM., Martinez G., Kiffin R., R.H. Brown and Glimcher L. (2009). “XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy”. Genes & Dev. 23:2294–2306. (Cover illustration) *Commented in Genes Dev. (2009), 23:2294-306. | | ABSTRACT
  • Matus S., Lisbona F., Torres M., Leon C., Thielen P., and Hetz C. (2008). The stress rheostat: Interplay between the Unfolded Protein Response (UPR) and Autophagy in neurodegeneration. Curr. Mol. Med. 8:157-172. #. | | ABSTRACT
  • Matus S, Burgos PV, Bravo-Zehnder M, Kraft R, Porras OH, Farías P, Barros LF, Torrealba F, Massardo L, Jacobelli S, González A. (2007). Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J Exp Med. 2007 Dec 24;204(13):3221-34. | | ABSTRACT