Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis

Naoki Mori, Yasutsugu Ishiba, Shinya Kubota, Akira Kobayashi, Tomomi Higashide, Margaret J. McLaren, George Inana

Research output: Contribution to journalArticle

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Abstract

PURPOSE. To characterize the time course of apoptosis and degeneration in a transgenic mouse model of retinal degeneration based on truncated mutant HRG4; to investigate the nature of binding of the mutant HRG4 to its target, ADPribosylation factor-like (ARL)2; to study its effects on the downstream molecules Binder-of-ARL2 (BART) and adenine nucleotide transporter (ANT)-1 and on the induction of apoptosis. METHODS. Saturation binding, microscopic morphometric, Western blot, immunofluorescence, and TUNEL analyses were used. RESULTS. Increased apoptosis did not occur until 20 months in the transgenic retina, consistent with the delayed-onset degeneration in this model. The truncated HRG4 protein exhibited approximately threefold greater affinity for ARL2 than the wildtype HRG4, likely resulting in nonfunctional sequestration of ARL2. A significant decrease in ARL2 was present by 20 months, accompanied by a 50% decrease in ANT-1 in the photoreceptor synaptic mitochondria, with evidence of mitochondrial dysfunction. Preapoptotic degeneration in the photoreceptor synapse was demonstrated with cytochrome c release and caspase 3 activation within the synapse - without evidence of TUNEL-positive apoptosis in the photoreceptor cell body - indicating an initial event in the synapse leading to apoptosis. Caspase 3 was activated in the accompanying secondary neuron, consistent with transsynaptic degeneration. CONCLUSIONS. The results support a novel mechanism of retinal degeneration in which preapoptotic degeneration starts in the photoreceptor synapse because of a deficiency in ANT-1 and spreads to the secondary neuron transsynaptically, followed by apoptosis and degeneration in the cell body of the photoreceptor.

Original languageEnglish
Pages (from-to)1281-1292
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number4
DOIs
StatePublished - Apr 1 2006

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Retinal Degeneration
Adenine Nucleotides
Apoptosis
Synapses
Mutation
In Situ Nick-End Labeling
Caspase 3
Neurons
Photoreceptor Cells
Transgenic Mice
Fluorescent Antibody Technique
Retina
Mitochondria
Western Blotting
Proteins

ASJC Scopus subject areas

  • Ophthalmology

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Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis. / Mori, Naoki; Ishiba, Yasutsugu; Kubota, Shinya; Kobayashi, Akira; Higashide, Tomomi; McLaren, Margaret J.; Inana, George.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 4, 01.04.2006, p. 1281-1292.

Research output: Contribution to journalArticle

Mori, Naoki ; Ishiba, Yasutsugu ; Kubota, Shinya ; Kobayashi, Akira ; Higashide, Tomomi ; McLaren, Margaret J. ; Inana, George. / Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 4. pp. 1281-1292.
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AU - Mori, Naoki

AU - Ishiba, Yasutsugu

AU - Kubota, Shinya

AU - Kobayashi, Akira

AU - Higashide, Tomomi

AU - McLaren, Margaret J.

AU - Inana, George

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N2 - PURPOSE. To characterize the time course of apoptosis and degeneration in a transgenic mouse model of retinal degeneration based on truncated mutant HRG4; to investigate the nature of binding of the mutant HRG4 to its target, ADPribosylation factor-like (ARL)2; to study its effects on the downstream molecules Binder-of-ARL2 (BART) and adenine nucleotide transporter (ANT)-1 and on the induction of apoptosis. METHODS. Saturation binding, microscopic morphometric, Western blot, immunofluorescence, and TUNEL analyses were used. RESULTS. Increased apoptosis did not occur until 20 months in the transgenic retina, consistent with the delayed-onset degeneration in this model. The truncated HRG4 protein exhibited approximately threefold greater affinity for ARL2 than the wildtype HRG4, likely resulting in nonfunctional sequestration of ARL2. A significant decrease in ARL2 was present by 20 months, accompanied by a 50% decrease in ANT-1 in the photoreceptor synaptic mitochondria, with evidence of mitochondrial dysfunction. Preapoptotic degeneration in the photoreceptor synapse was demonstrated with cytochrome c release and caspase 3 activation within the synapse - without evidence of TUNEL-positive apoptosis in the photoreceptor cell body - indicating an initial event in the synapse leading to apoptosis. Caspase 3 was activated in the accompanying secondary neuron, consistent with transsynaptic degeneration. CONCLUSIONS. The results support a novel mechanism of retinal degeneration in which preapoptotic degeneration starts in the photoreceptor synapse because of a deficiency in ANT-1 and spreads to the secondary neuron transsynaptically, followed by apoptosis and degeneration in the cell body of the photoreceptor.

AB - PURPOSE. To characterize the time course of apoptosis and degeneration in a transgenic mouse model of retinal degeneration based on truncated mutant HRG4; to investigate the nature of binding of the mutant HRG4 to its target, ADPribosylation factor-like (ARL)2; to study its effects on the downstream molecules Binder-of-ARL2 (BART) and adenine nucleotide transporter (ANT)-1 and on the induction of apoptosis. METHODS. Saturation binding, microscopic morphometric, Western blot, immunofluorescence, and TUNEL analyses were used. RESULTS. Increased apoptosis did not occur until 20 months in the transgenic retina, consistent with the delayed-onset degeneration in this model. The truncated HRG4 protein exhibited approximately threefold greater affinity for ARL2 than the wildtype HRG4, likely resulting in nonfunctional sequestration of ARL2. A significant decrease in ARL2 was present by 20 months, accompanied by a 50% decrease in ANT-1 in the photoreceptor synaptic mitochondria, with evidence of mitochondrial dysfunction. Preapoptotic degeneration in the photoreceptor synapse was demonstrated with cytochrome c release and caspase 3 activation within the synapse - without evidence of TUNEL-positive apoptosis in the photoreceptor cell body - indicating an initial event in the synapse leading to apoptosis. Caspase 3 was activated in the accompanying secondary neuron, consistent with transsynaptic degeneration. CONCLUSIONS. The results support a novel mechanism of retinal degeneration in which preapoptotic degeneration starts in the photoreceptor synapse because of a deficiency in ANT-1 and spreads to the secondary neuron transsynaptically, followed by apoptosis and degeneration in the cell body of the photoreceptor.

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