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Distinct retinal deficits in a zebrafish pyruvate dehydrogenase-deficient mutant


Maurer, C M; Schönthaler, H B; Mueller, K P; Neuhauss, S C F (2010). Distinct retinal deficits in a zebrafish pyruvate dehydrogenase-deficient mutant. Journal of Neuroscience, 30(36):11962-11972.

Abstract

Mutations in ubiquitously expressed metabolic genes often lead to CNS-specific effects, presumably because of the high metabolic demands of neurons. However, mutations in omnipresent metabolic pathways can conceivably also result in cell type-specific effects because of cell-specific requirements for intermediate products. One such example is the zebrafish noir mutant, which we found to be mutated in the pdhb gene, coding for the E1 β subunit of the pyruvate dehydrogenase complex. This vision mutant is described as blind and was isolated because of its vision defect-related darker appearance. A detailed morphological, behavioral, and physiological analysis of the phenotype revealed an unexpected specific effect on the retina. Surprisingly, the cholinergic amacrine cells of the inner retina are affected earlier than the photoreceptors. This might be attributable to the inability of these cells to maintain production of their neurotransmitter acetylcholine. This is reflected in an earlier loss of motion vision, followed only later by a general loss of light perception. Since both characteristics of the phenotype are attributable to a loss of acetyl-CoA production by pyruvate dehydrogenase, we used a ketogenic diet to bypass this metabolic block and could indeed partially rescue vision and prolong survival of the larvae. The noir mutant provides a case for a systemic disease with ocular manifestation with a surprising specific effect on the retina given the ubiquitous requirement for the mutated gene.

Mutations in ubiquitously expressed metabolic genes often lead to CNS-specific effects, presumably because of the high metabolic demands of neurons. However, mutations in omnipresent metabolic pathways can conceivably also result in cell type-specific effects because of cell-specific requirements for intermediate products. One such example is the zebrafish noir mutant, which we found to be mutated in the pdhb gene, coding for the E1 β subunit of the pyruvate dehydrogenase complex. This vision mutant is described as blind and was isolated because of its vision defect-related darker appearance. A detailed morphological, behavioral, and physiological analysis of the phenotype revealed an unexpected specific effect on the retina. Surprisingly, the cholinergic amacrine cells of the inner retina are affected earlier than the photoreceptors. This might be attributable to the inability of these cells to maintain production of their neurotransmitter acetylcholine. This is reflected in an earlier loss of motion vision, followed only later by a general loss of light perception. Since both characteristics of the phenotype are attributable to a loss of acetyl-CoA production by pyruvate dehydrogenase, we used a ketogenic diet to bypass this metabolic block and could indeed partially rescue vision and prolong survival of the larvae. The noir mutant provides a case for a systemic disease with ocular manifestation with a surprising specific effect on the retina given the ubiquitous requirement for the mutated gene.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Retina, Zebrafish, Pyruvate Dehydrogenase, Leigh Syndrome, Vision
Language:English
Date:8 September 2010
Deposited On:09 Nov 2010 12:12
Last Modified:05 Apr 2016 14:15
Publisher:Society for Neuroscience
ISSN:0270-6474
Additional Information:Holder of copyright: The Society for Neuroscience
Publisher DOI:10.1523/JNEUROSCI.2848-10.2010
PubMed ID:20826660
Permanent URL: http://doi.org/10.5167/uzh-35810

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