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

@article{citeulike:1365355, 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.}, address = {Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.}, author = {Mori, N. and Ishiba, Y. and Kubota, S. and Kobayashi, A. and Higashide, T. and McLaren, M. J. and Inana, G. }, citeulike-article-id = {1365355}, doi = {10.1167/iovs.05-0493}, issn = {0146-0404}, journal = {Invest Ophthalmol Vis Sci}, keywords = {ant, arl2, bart}, month = {April}, number = {4}, pages = {1281--1292}, posted-at = {2007-06-05 10:46:34}, priority = {2}, title = {Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis.}, url = {http://dx.doi.org/10.1167/iovs.05-0493}, volume = {47}, year = {2006} }

TY - JOUR ID - citeulike:1365355 L3 - citeulike-article-id:1365355 TI - Truncation mutation in HRG4 (UNC119) leads to mitochondrial ANT-1-mediated photoreceptor synaptic and retinal degeneration by apoptosis. JF - Invest Ophthalmol Vis Sci VL - 47 IS - 4 SP - 1281 EP - 1292 AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. SN - 0146-0404 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, 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. KW - ant KW - arl2 KW - bart AU - Mori, N AU - Ishiba, Y AU - Kubota, S AU - Kobayashi, A AU - Higashide, T AU - McLaren, MJ AU - Inana, G PY - 2006/04// UR - http://dx.doi.org/10.1167/iovs.05-0493 ER -