Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration.
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.
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Blanca
B
Arango-Gonzalez
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Dragana
D
Trifunović
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Ayse
A
Sahaboglu
Department of Neurobiology, University of Oldenburg, Oldenburg, Germany.
Katharina
K
Kranz
Center for Integrated Protein Science Munich and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Stylianos
S
Michalakis
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany; Division of Ophthalmology, Department of Clinical Sciences, University of Lund, Lund, Sweden.
Pietro
P
Farinelli
Center for Integrated Protein Science Munich and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Susanne
S
Koch
Center for Integrated Protein Science Munich and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Fred
F
Koch
Institute for Research in Ophthalmology, Sion, Switzerland.
Sandra
S
Cottet
Department of Neurobiology, University of Oldenburg, Oldenburg, Germany.
Ulrike
U
Janssen-Bienhold
Department of Neurobiology, University of Oldenburg, Oldenburg, Germany.
Karin
K
Dedek
Center for Integrated Protein Science Munich and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Martin
M
Biel
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany; Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany.
Eberhart
E
Zrenner
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany; Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany.
Thomas
T
Euler
Division of Ophthalmology, Department of Clinical Sciences, University of Lund, Lund, Sweden.
Per
P
Ekström
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Marius
M
Ueffing
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
François
F
Paquet-Durand
D000818:Animals; D030801:Animals, Genetically Modified; D002154:Calpain / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000502:physiology; D055537:Light Signal Transduction / Q000235:genetics; D051379:Mice; D009154:Mutation; D011064:Poly Adenosine Diphosphate Ribose / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D051381:Rats; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology*
D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D006655:Histone Deacetylases; D006152:Cyclic GMP