Selective assoction of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria

Velde CV; Miller TM; Cashman NRCleveland DW

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Selective assoction of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria

机译：Selective assoction of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria

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Mutations in copper/zinc superoxide dismutase (SOD1) are causative for dominantly inherited amyotrophic lateral sclerosis (ALS). Despite high variability in biochemical properties among the disease-causing mutants, a proportion of both dismutase-active and -inactive mutants are stably bound to spinal cord mitochondria. This mitochondrial proportion floats with mitochondria rather than sedimenting to the much higher density of protein, thus eliminating coincidental cosedimentation of protein aggregates with mitochondria. Half of dismutase-active and approximate to 90 of dismutase-inactive mutant SOD1 is bound to mitochondrial membranes in an alkali- and salt-resistant manner. Sensitivity to proteolysis and immunoprecipitation with an antibody specific for misfolded SOD1 demonstrate that in all mutant SOD1 models, misfolded SOD1 is deposited onto the cytoplasmic face of the outer mitochondrial membrane, increasing antigenic accessibility of the normally structured electrostatic loop. Misfolded mutant SOD1 binding is both restricted to spinal cord and selective for mitochondrial membranes, implicating exposure to mitochondria of a misfolded mutant SOD1 conformer mediated by a unique, tissue-selective composition of cytoplasmic chaperones, components unique to the cytoplasmic face of spinal mitochondria to which misfolded SOD1 binds, or misfolded SOD1 conformers unique to spinal cord that have a selective affinity for mitochondrial membranes.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2008年第10期|4022-4027|共6页
作者
Velde CV; Miller TM; Cashman NRCleveland DW;
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作者单位

Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.;

Univ British Columbia, Univ British Columbia Hosp, Dept Med Neurol, Vancouver, BC V6T 2B5, Canada.;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
degeneration; motor neuron disease; superoxide dismutase;

Selective assoction of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria

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