Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration

• Published in: PloS one Vol. 9; no. 11; p. e112142
• Main Authors: Arango-Gonzalez, Blanca, Trifunović, Dragana, Sahaboglu, Ayse, Kranz, Katharina, Michalakis, Stylianos, Farinelli, Pietro, Koch, Susanne, Koch, Fred, Cottet, Sandra, Janssen-Bienhold, Ulrike, Dedek, Karin, Biel, Martin, Zrenner, Eberhart, Euler, Thomas, Ekström, Per, Ueffing, Marius, Paquet-Durand, François
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.11.2014; Public Library of Science (PLoS)
• Subjects: Adenosine diphosphate; Animal models; Animals; Animals, Genetically Modified; Apoptosis; Biology and Life Sciences; Blindness; Calpain; Calpain - physiology; Cell death; Cell Death - genetics; Cell Death - physiology; Clinical Medicine; Cyclic GMP; Cyclic GMP - physiology; Degeneration; Disease Models, Animal; Guanosine; Histone deacetylase; Histone Deacetylases - physiology; Klinisk medicin; Light Signal Transduction - genetics; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine and Health Sciences; Mice; Mortality; Mutants; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurosciences; Oftalmologi; Ophthalmology; Poly Adenosine Diphosphate Ribose - physiology; Poly(ADP-ribose) Polymerases - physiology; Polymerase; Rats; Retina; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - physiopathology; Ribose; Rodents; Science; Sweden; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112142

Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.