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
Undergraduate Students: Marcela Escandón Bernal • Álvaro Brito Arratia • Felipe Gómez Ibarra • Juan Francisco Roa
Research Assistants: Pamela Farfán González, Biochemist
Post-doctoral Fellows: Paulina Falcón Urrutia • Nicolás Martinez Alarcón

FORMER LAB MEMBERS

Luis Osorio. PhD Student. Universidad de Chile.
Carolina Jerez. Biochemist. Research Assistant.
Yamil Marambio. Biochemist. Research Assistant.
Natalia Muñoz. Chemistry Analyst. Research Assistant.

COLLABORATIONS

National Collaborations:
• Dr. Claudio Hetz. Universidad de Chile.
• Dr. Felipe Court. Universidad Mayor.
• Dr. Rene Vidal. Universidad Mayor.
• Dr. Patricio Olguín (Faculty of Medicine, Universidad de Chile).

International Collaborations:
• Dr. Mauro Costa-Mattioli. Baylor University.
• Dr. Lionel Muller Igaz. Universidad de Buenos Aires
• Dr. Francisco Herrera. Trancura Biosciences.

SELECTED PUBLICATIONS

  • Martínez NW, FE Gomez, and Matus S. “The potential role of Protein Kinase R as a regulator of age-related neurodegeneration” Front. Aging Neurosci. (2021) Accepted Manuscript. DOI: 10.3389/fnagi.2021.638208 | | ABSTRACT
  • Vidal RL, Sepulveda D, Troncoso-Escudero P, Garcia-Huerta P, Gonzalez C, Plate L, Carolina Jerez C, Canovas J, Rivera CA, Castillo V, Cisternas M, Leal S, Martinez A, Grandjean J, Sonia D, Lashuel HA, Martin AJM, Latapiat V, Matus S, S Sardi P, Wiseman RP, Hetz C. “Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration” Mol Ther. (2021) Feb 3; S1525-0016(21)00067-8. DOI: 10.1016/j.ymthe.2021.01.033. | | ABSTRACT
  • Barrera MJ, Aguilera S, Castro I, Matus S, Carvajal P, Molina C, González S, Jara D, Hermoso M, and María Julieta González. “Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjögren’s syndrome”. Rheumatology. (2020) 1–12. DOI: 10.1093/rheumatology/keaa670. | | ABSTRACT
  • Falcón P, Escandón M, Brito Á, Matus S. Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging. Oxid Med Cell Longev. (2019) May 22;2019:5730532. doi: 10.1155/2019/5730532. | PDF | ABSTRACT
  • Beltran S, Nassif M, Vicencio E, Arcos J, Labrador L, Cortes BI, Cortez C, Bergmann CA, Espinoza S, Hernandez MF, Matamala JM, Bargsted L, Matus S, Rojas-Rivera D, Bertrand MJM, Medinas DB, Hetz C, Manque PA, Woehlbier U. Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis. Mol Neurodegener. (2019) 14(1):14. doi.org/10.1186/s13024-019-0313-9 | PDF | ABSTRACT
  • Montoya A, Elgueta D, Campos J, Chovar O, Falcón P, Matus S, Alfaro I, Bono MR, Pacheco R.J Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation. Neuroinflammation. (2019) 16(1):258. doi: 10.1186/s12974-019-1652-8. | PDF | ABSTRACT
  • 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. Genome-wide circulating microRNA expression profiling reveals potential biomarkers for amyotrophic lateral sclerosis. Neurobiol Aging. (2018) 64:123-138. doi: 10.1016/j.neurobiolaging.2017.12.020. | PDF | ABSTRACT
  • Bargsted L, Medinas DB, Martínez Traub F, Rozas P, Muñoz N, Nassif M, Jerez C, Catenaccio A, Court FA, Hetz C, Matus S. Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model. Sci Rep. (2017) 7(1):14266. doi: 10.1038/s41598-017-14399-5. | PDF | ABSTRACT
  • 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