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

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, ADP-ribosylation 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 wild-type 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.

• Authors: Naoki Mori, Yasutsugu Ishiba, Shinya Kubota, Akira Kobayashi, Tomomi Higashide, Margaret J McLaren, George Inana
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 47 Issue 4 Pg. 1281-92 (Apr 2006) ISSN: 0146-0404 [Print] United States
• PMID: 16565359 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Adenine Nucleotide Translocator 1
• Codon, Nonsense
• Intracellular Signaling Peptides and Proteins
• Microtubule Proteins
• Unc119 protein, mouse
• Cytochromes c
• Casp3 protein, mouse
• Caspase 3
• Caspases

Topics

• Adaptor Proteins, Signal Transducing
• Adenine Nucleotide Translocator 1 (deficiency)
• Animals
• Apoptosis
• Blotting, Western
• Caspase 3
• Caspases (metabolism)
• Codon, Nonsense
• Cytochromes c (metabolism)
• Enzyme Activation
• In Situ Nick-End Labeling
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• Microtubule Proteins (genetics)
• Mitochondria (metabolism)
• Photoreceptor Cells, Vertebrate (metabolism)
• Retinal Degeneration (genetics, metabolism)
• Synapses (metabolism)