Distinct retinal deficits in a zebrafish pyruvate dehydrogenase-deficient mutant.
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 beta 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.
Maurer
Colette M
CM
University of Zurich, Institute of Molecular Life Sciences, Neuroscience Center Zurich and Center for Integrative Human Physiology, Zurich, Switzerland.
Schönthaler
Helia B
HB
Mueller
Kaspar P
KP
Neuhauss
Stephan C F
SC
D000613:Aminobutyrates / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001224:Aspartic Acid / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004252:DNA Mutational Analysis; D055423:Diet, Ketogenic / Q000379:methods; D004195:Disease Models, Animal; D004596:Electroretinography / Q000379:methods; D004625:Embryo, Nonmammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007814:Larva; D009068:Movement / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D017120:Nystagmus, Optokinetic / Q000235:genetics / Q000502:physiology; D010775:Photic Stimulation / Q000379:methods; D011767:Pyruvate Decarboxylase / Q000172:deficiency*; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D012164:Retinal Diseases / Q000175:diagnosis* / Q000178:diet therapy / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D029961:Zebrafish Proteins; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D011767:Pyruvate Decarboxylase; C012729:2-amino-4-phosphonobutyric acid
Neuron. 2007 Jul 19;55(2):179-86
17640521
J Vis Exp. 2008 Oct 03;(20):
19078942
J Neurocytol. 2001 Jul;30(7):551-92
12118162
Dev Biol. 2002 Aug 15;248(2):307-18
12167406
Brain Res. 2005 Oct 5;1058(1-2):17-29
16150425
Brain Res Bull. 2005 Sep 15;66(4-6):421-5
16144624
Exp Eye Res. 2007 Aug;85(2):175-84
17618621
Invest Ophthalmol Vis Sci. 1976 Sep;15(9):700-25
986765
J Physiol. 2008 Sep 15;586(18):4371-6
18617561
Mol Genet Metab. 2001 Nov;74(3):293-302
11708858
Invest Ophthalmol Vis Sci. 2005 Jan;46(1):137-42
15623766
J Neurosci Methods. 2010 Jan 30;186(1):29-34
19900474
Curr Biol. 2010 Feb 23;20(4):381-6
20153194
Invest Ophthalmol Vis Sci. 1987 Dec;28(12):1888-904
3316105
Curr Opin Neurobiol. 2001 Aug;11(4):475-80
11502395
J Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216-21
14874135
PLoS One. 2008 Jul 23;3(7):e2748
18648503
J Biol Chem. 1994 Jul 8;269(27):17954-9
8027053
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14512-7
9405644
J Neurophysiol. 2005 Jan;93(1):84-93
15229213
Dis Model Mech. 2010 May-Jun;3(5-6):343-53
20335444
Neuron. 2001 Jun;30(3):771-80
11430810
Science. 1999 Mar 5;283(5407):1482-8
10066162
Trends Cardiovasc Med. 2009 Feb;19(2):38-43
19577710
Exp Eye Res. 2009 Mar;88(3):553-60
19084520
J Neurophysiol. 1996 Dec;76(6):3842-9
8985882
J Neurosci. 1992 Mar;12(3):840-53
1312136
Prog Retin Eye Res. 1998 Jul;17(3):429-42
9695799
Vision Res. 1998 May;38(10):1335-9
9667001
J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S339-43
19924563
J Neurosci Methods. 2004 May 30;135(1-2):205-10
15020104
Trends Neurosci. 2005 Aug;28(8):395-6
15979167
Zebrafish. 2004;1(2):121-31
18248224
J Neurosci. 1995 Jul;15(7 Pt 2):5179-91
7623144
Curr Biol. 2008 Dec 23;18(24):1917-21
19084410
Curr Opin Neurobiol. 2002 Aug;12(4):405-10
12139988
Dev Biol. 2005 Sep 1;285(1):138-55
16231865
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4584-9
15070761
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10545-9
7479837
Nature. 2005 Dec 15;438(7070):960-6
16355161
Invest Ophthalmol Vis Sci. 2000 Feb;41(2):337-48
10670460
J Neurophysiol. 2005 Jan;93(1):94-107
15229214
J Neurosci. 1999 Oct 1;19(19):8603-15
10493760
Development. 1996 Dec;123:1-36
9007226
Development. 1996 Dec;123:369-89
9007256
J Physiol. 2009 Sep 15;587(Pt 18):4481-95
19651763
J Neurophysiol. 2008 Oct;100(4):1995-2004
18684905