Objective/Rationale:
Our general objective is to investigate the role of a specific component of a cellular stress responses linked to organelle damage, the Unfolded Protein Response (UPR), in the development of Parkinson's disease. We intend to define the possible therapeutic benefits of alleviating cellular stress using gene therapy strategies in a disease context in vivo.
Project Description:
Parkinson's disease (PD) is the second most common chronic, progressive neurodegenerative disease, characterized by impairment of motor control as a result from extensive neuron death. The primary mechanism responsible for the progressive neuronal loss in PD remains unknown. Clues have been obtained from families who have a genetic form of PD that is accompanied by a mutation in an important protein called alpha-synuclein. It has been suggested that perturbation in the function of a subcellular organelle called the endoplasmic reticulum (ER) may determine the pathological effects of alpha-synuclein and other genetic forms of PD. In this target validation project we aim to define the contribution of this stress pathway to PD using pre-clinical models of genetic and sporadic forms of the PD. By employing a gene therapy strategy to manipulate the levels of an essential factor of ER stress responses (termed XBP-1), we intend to asses the possible therapeutic benefits of targeting the pathway in PD. This work will help validating a novel therapeutic target, in addition to foster developing an experimental therapy to treat this important disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We plan to define for the first time the actual role of the UPR, in the development of PD. This research aims to determine whether or not the UPR is a valid target to design therapeutic strategies to treat PD patients.
Anticipated Outcome:
This research grant aims to perform a systematic study to determine the impact of targeting the UPR locally in the adult substantia nigra in the development of hereditary and sporadic Parkinson's disease.
Final Outcome
It has been suggested that perturbation in the function of a subcellular organelle called the endoplasmic reticulum (ER) may determine the pathological effects of alpha-synuclein and other genetic forms of PD. In this target validation project we aimed to define the contribution of this stress pathway to PD using pre-clinical models of genetic and sporadic forms of the PD. By employing a gene therapy strategy to manipulate the levels of an essential factor of ER stress responses (termed XBP-1), we have defined possible therapeutic benefits of targeting the pathway in PD. We observed that the delivery of an active form of XBP-1 into the subtantia nigra of the model significantly protected neurons against the development of experimental PD. Moreover, using strategies that eliminate this factor in neurons we uncovered a fundamental role of XBP-1 in the normal function and survival of dopaminergic neurons. Our results indicate that the ER stress pathway is a potential therapeutic target to treat PD. Importantly, the tools developed in this project for gene therapy have great promise for possible use in clinical trials since the vectors employed are well suited for this purpose and are currently been tested in eight independent clinical trials in PD patients.
PUBLICATIONS
Woehlbier U. and Hetz C. (2011). Woehlbier U, Hetz C. 2011 Modulating stress responses by the UPRosome: A matter of life and death. Trends Biochem Sci. 36(6):329-37.
Hetz C, Martino F, Rodriguez, and Glimcher LH. (2011). The Unfolded Protein Response: Integrating stress signals through the stress sensor IRE1a. Physiological Reviews. In press
Torres M, Encina G, Soto C and Hetz C. 2011Abnormal calcium homeostasis and protein folding stress at the ER: A common factor in familial and infectious prion disorders. Communicative & Integrative Biology 4:3, 1-4.
Nassif M. and Hetz C. (2011). Targeting autophagy in ALS: a complex mission. Autophagy, 1;7(4).
Barrientos S.A., Martinez N.W., Yoo S., Jara, J.S., Zamorano S, Hetz, C., Twiss J.L. Alvarez J., Court F. A. Axonal degeneration is mediated by the mitochondrial permeability transition pore. J. Neurosci. 2011 January; 31(3):966 –978
Matus, S., Hetz, C., Glimcher L. Protein folding stress in neurodegenerative diseases: a glimpse into the ER (2011) Curr Opin Cell Biol. 2011 23(2):239–252
Vidal R., Caballero B., Couve A., and Hetz C. “Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease”, Curr Mol Med. 2011 Feb;11(1):1-12.
Rodriguez D, Rojas-Rivera D, Hetz C.Integrating stress signals at the endoplasmic reticulum: The BCL-2 protein family rheostat. Biochim Biophys Acta. 2011 Apr;1813(4):564-74. Epub 2010 Nov 29.
Torres M., Matus S., Arminsen R., Stitzin A., Soto C., and Hetz C. (2010). Prion Replication affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress. PlosOne 5:12 (12):e15658- e15658
Melissa Nassif, Soledad Matus, Karen Castillo, and Claudio Hetz (2010), “Amyotrophic lateral sclerosis pathogenesis: a journey through the secretory pathway”, Antioxidants & Redox Signaling, Antioxid Redox Signal. 2010 Dec 15;13(12):1955-89.
Andres Klein, Matías Mosqueira, Gabriela Martinez, Fermín Robledo, Marcela González, Benjamín Caballero, Gonzalo I. Cancino, Alejandra R. Alvarez, Claudio Hetz and Silvana Zanlungo (2010), “Lack of activation of the Unfolded Protein Response (UPR) in mouse and cellular models of Niemann-Pick type C disease.”, Neurodegener Dis. 2010 Aug 13. [Epub ahead of print]
Rojas D., Caballero, B., Zamorano S., Lisbona F., and Hetz C (2010) Alternative Functions of the BCL-2 Protein Family at the Endoplasmic Reticulum. Claudio Hetz Protein Family at the Endoplasmic Reticulum. Adv Exp Med Biol. 2010;687:33-47.
MEETINGS
Valdés P.,Martínez A.,Hetz C. 2010. XBP-1 Deficiency protects against 6-OHDA neurotoxicity in mice possibly through the upregulation of ER chaperones and autophagy. Annual meeting of The Biology Society of Chile. November 1-5. Chile
Hetz C. 2011. Homeostatic connection between the Unfolded Protein Response (UPR) and autophagy in neurodegeneration. Keystone Meeting Autophagy, March 27- April1, Vancouver Canadá.
Rodríguez D, Zamorano S, Lisbona F, Rojas D, Arminsen R, Cubillos-Ruiz J, Irrazabal T, Gonzalez-Billault C, and Hetz C. 2011. BH3-only proteins control the sustained signaling of the Unfolded Protein Response sensor IRE1α. Signaling in cell death survival, proliferation and degeneration. Queens Collage Foundation. June 10-13, Sao Paulo, Brazil.
Rodríguez D, Zamorano S, Lisbona F, Rojas D, Arminsen R, Cubillos-Ruiz J, Irrazabal T, Gonzalez-Billault C, and Hetz C. 2011. BH3-only proteins control the sustained signaling of the Unfolded Protein Response sensor IRE1α. FASEB Research Conferences Vermont Academy From Unfolded Proteins in the Endoplasmic Reticulum to Disease. June 12-17, Vermont, USA.
Hetz C. 2011. Organelle Stress and Protein Misfolding Disorders affecting the Nervous System. Symposium “A Commitment to Lineage”, Harvard University (Dr. Laurie Glimcher) April 15, Boston, USA.
Hetz C. 2011. Homeostatic connection between the Unfolded Protein Response (UPR) and autophagy in neurodegeneration. New Frontiers in Neurodegeneration, UMASS (Dr. Robert Brown) May 18-20, Boston, USA.
Hetz C. 2011 Homeostatic connection between the Unfolded Protein Response (UPR) and autophagy in neurodegeneration. École Polytechnique Fédérale de Lausanne. (Dr. Patrick Aebischer)August 22 - 29, Switzerland.
Vidal R, Figueroa A, Court F, Thielen P, Wirth C, Cuervo AM, Glimcher L.H., and Hetz C. 2011 D434 Targeting the UPR transcription factor XBP1 protects against experimental Huntington's disease by enhancing mutant Huntington clearance by autophagy. 8th IBRO World Congress of Neuroscience. July 14-18, Florence, Italy.
Vidal R.,Figueroa A.,Thielen P.,Hetz C. 2010. XBP-1 deficiency leads to autophagy-mediated degradation of protein aggregates related to Huntington´s diseases. 40th Annual Meeting of the Society for Neuroscience. November 13-17. San Diego, United States.