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Power Failure Leads to Paralysis

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Science Translational Medicine  08 Sep 2010:
Vol. 2, Issue 48, pp. 48ec140
DOI: 10.1126/scitranslmed.3001655

Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, is always fatal—usually after years of progressive degeneration of the upper motor neurons of the brain and the lower motor neurons of the spinal cord. A small proportion of individuals with familial (inherited) ALS carry mutations in the gene encoding cytoplasmic Cu/Zn superoxide dismutase (SOD1). The basis of sporadic (noninherited) ALS has not been clear, although mitochondria are dysfunctional in both sporadic and familial ALS patients and in mouse models expressing mutant SOD1. The mechanism responsible for SOD1-mediated mitochondrial toxicity has remained uncertain, however. A recent study by Israelson and colleagues now suggests that mutant (but not normal) SOD1 may affect ion conductances through the voltage-dependent anion channel (VDAC1), which is a key outer mitochondrial membrane protein that regulates metabolic interactions with the rest of the cell, calcium transport, and apoptosis, among other functions.

The authors evaluated the physical interaction of SOD1 and VDAC1, as well as the effects of mutant SOD1 on VDAC1 ion conductances. In mitochondria from rats expressing two different ALS-linked SOD1 mutants, they found that VDAC1 coprecipitated with mutant SOD1 but not wild-type SOD1. An antibody that recognizes a disease-specific epitope present only on misfolded mutant SOD1 (found in inherited ALS) selectively coprecipitated mutant SOD1 with VDAC1. The mutant SOD1 substantially attenuated VDAC1 ion channel conductances, unlike wild-type SOD1, and did so only when SOD1 was added to the cis side of the lipid bilayer, suggesting that this interaction occurs in vivo on the cytosolic face of VDAC1. Furthermore, uptake of ADP (but not calcium) into mitochondria (which primarily occurs through VDAC1) was reduced in the spinal cord of SOD1-mutant rats. Lastly, mice carrying mutant SOD1 and reduced numbers of active VDAC1 alleles exhibited accelerated disease onset and early progression, as manifested by weight loss thought to reflect denervation-induced muscle atrophy.

These results suggest that misfolded SOD1 affects transport of ions and other molecules through VDAC1, setting in motion deficits in cellular energetics that lead to the death of motor neurons and disease progression. Perhaps a breakthrough in the treatment of this illness will arise from redressing the loss of power in the motor neurons of the central nervous system.

A. Israelson et al., Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67, 575–587 (2010). [Abstract]

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