In the first paper, Don Cleveland of the University of California, San Diego, and colleagues at several other institutions, showed that mutant SOD1 protein, but not wild-type SOD1, finds a home in the mitochondria of spinal cord neurons. The researchers, led by first author Jian Liu, looked at SOD1 localization in a series of transgenic SOD1 mouse mutants, with a range of cytoplasmic concentrations and toxicities. Interestingly, about the same amount of mutant SOD1 localized to the mitochondria irrespective of the protein’s concentration in the cytoplasm of motor neurons.

In particular, the mutant proteins associated with mitochondrial membrane proteins, especially those on the outer part of the membrane. In skeletal muscle, whole brain, or liver, mutant SOD1 was not to be found associated with mitochondria. The researchers report that mutant SOD1 begins to accumulate in and on mitochondria along with the earliest pathology, before disease onset. It seems to make no difference whether the mutant SOD1 retains the catalytic capabilities of wild-type SOD1 or not.

Because they found no wild-type SOD1 associated with spinal motor neuron mitochondria, the authors suggest that the selective import of the mutant SOD1 in motor neurons provides a compelling explanation for the specificity of the disease for these cells. (Note, however, that other researchers have reported finding wild-type SOD1 in mitochondria; see Mattiazi et al., 2002). "We propose that the universal association of SOD1 mutant with mitochondria exclusively within affected tissues represents the common property of these mutants that initiates a cascade of damage," write the authors.

Among the potential damage that the authors point to, they emphasize the fact that mitochondria are "the gatekeepers of caspase-directed cell death." And, indeed, a study in the same issue finds that mutant SOD1 makes the motor neurons more vulnerable to apoptosis.

Following up evidence that mutant SOD1 affects levels of the anti-apoptotic protein Bcl-2—which happens to reside on the outside of the mitochondrial membrane—Bob Brown and his associates at Harvard University and Massachusetts General Hospital in Charlestown found evidence that both wild- type and mutant SOD1 interact with Bcl-2 in vitro. Moreover, mutant SOD1 binds to Bcl-2 in spinal cord mitochondria from both mutant SOD1-transgenic mice and human ALS.

The obvious implication is that SOD1 could hasten cell death in vivo if it interfered with Bcl-2 in a significant way. Indeed, the scientists found that, in mitochondria from both mutant SOD1 mice and human spinal cord, but not from liver, SOD1-containing aggregates trap significant amounts of Bcl-2.

"These observations suggest the hypothesis that mutant protein captures Bcl-2 within unstable aggregates, depleting the motor neurons of this anti-apoptotic protein," write the authors. They also note that Bcl-2 is important in maintaining mitochondrial membrane potential, suggesting another avenue of disruption by mutant SOD1 in motor neurons.—Hakon Heimer.

References:
Liu J, Lillo C, Jonsson PA, Velde CV, Ward CM, Miller TM, Subramaniam JR, Rothstein JD, Marklund S, Andersen PM, Brannstrom T, Gredal O, Wong PC, Williams DS, Cleveland DW. Toxicity of Familial ALS-Linked SOD1 Mutants from Selective Recruitment to Spinal Mitochondria. Neuron. 2004 Jul 8;43(1):5-17. Abstract

Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH Jr. Abstract Amyotrophic Lateral Sclerosis-Associated SOD1 Mutant Proteins Bind and Aggregate with Bcl-2 in Spinal Cord Mitochondria. Neuron. 2004 Jul 8;43(1):19-30. Abstract