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PLoS One. 2014 Nov 13;9(11):e112142. doi: 10.1371/journal.pone.0112142. eCollection 2014.

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

Author information

1
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
2
Department of Neurobiology, University of Oldenburg, Oldenburg, Germany.
3
Center for Integrated Protein Science Munich and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
4
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany; Division of Ophthalmology, Department of Clinical Sciences, University of Lund, Lund, Sweden.
5
Institute for Research in Ophthalmology, Sion, Switzerland.
6
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany; Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany.
7
Division of Ophthalmology, Department of Clinical Sciences, University of Lund, Lund, Sweden.

Abstract

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.

PMID:
25392995
PMCID:
PMC4230983
DOI:
10.1371/journal.pone.0112142
[Indexed for MEDLINE]
Free PMC Article

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