Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis

Danilo B Medinas; Jose V González; Paulina Falcon; Claudio Hetz

doi:10.3389/fnmol.2017.00216

Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis

Front Mol Neurosci. 2017 Jul 5:10:216. doi: 10.3389/fnmol.2017.00216. eCollection 2017.

Authors

Danilo B Medinas^{1

2

3}, Jose V González^{1

2

3}, Paulina Falcon^{1

2

3}, Claudio Hetz^{1

2

3

4

5}

Affiliations

¹ Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of ChileSantiago, Chile.
² Faculty of Medicine, Biomedical Neuroscience Institute, University of ChileSantiago, Chile.
³ Center for Geroscience, Brain Health and MetabolismSantiago, Chile.
⁴ Buck Institute for Research on AgingNovato, CA, United States.
⁵ Department of Immunology and Infectious Diseases, Harvard School of Public HealthBoston, MA, United States.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER) stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). Inositol-requiring enzyme 1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration.

Keywords: ALS; ER stress; IRE1α; UPR; protein aggregation.