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Comment
. 2004 Apr 20;101(16):5701-2.
doi: 10.1073/pnas.0401934101. Epub 2004 Apr 12.

A possible therapeutic target for Lou Gehrig's disease

Soumya S Ray  1 , Peter T Lansbury Jr
Affiliations
Comment

A possible therapeutic target for Lou Gehrig's disease

Soumya S Ray et al. Proc Natl Acad Sci U S A. .
No abstract available

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Figures

Fig. 1.
Fig. 1.
The WT and A4V dimers differ slightly at the dimer interface. Ribbon diagrams of WT SOD1 (Upper, green) and A4V SOD1 (Lower, in red) (3). Dimers are depicted as being in equilibrium with a structured monomer that, in the absence of the other subunit, is likely to unfold partially or completely. The WT dimer is much more stable than the A4V dimer (4). Residue Val-4 is highlighted in the A4V structure. The A4V dimer, unlike the WT dimer, does not follow perfect twofold symmetry.
Fig. 2.
Fig. 2.
SOD1 dimer dissociation may be the first step in ALS pathogenesis. (Upper) A proposal, discussed in the text, in which A4V dimer (left subunit shows overlay of WT and A4V backbones) dissociation is the first step in SOD1 aggregate formation (an electron microscopy image of A4V aggregates including pore-like and large spherical structures formed in vitro is shown). It is unknown whether the folded monomer (shown), a partially unfolded monomer (not shown), or the alternative dimer detected by small-angle x-ray scattering is the building block of the aggregate (3). We and others have proposed that SOD1 aggregates initiate motor neuron death and ALS. (Lower Left) The disulfide-bonded variant of A4V (perspective is different from A4V dimer at top in order to show disulfide bond; arrow) does not aggregate (4). Thus, a drug-like molecule could bind at the A4V dimer interface and stabilize the A4V dimer (by slowing the rate of dissociation), thus decreasing the concentration of the monomer and slowing aggregation. Once such compounds have been identified, it will be possible to test whether they also delay onset and/or slow the progression of ALS in mouse models.
See this image and copyright information in PMC

Comment on

References

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    1. Ray, S. S., Nowak, R. J., Strokovich, K., Brown, R. H., Jr., Walz, T. & Lansbury, P. T., Jr. (2004) Biochemistry 39, in press. - PubMed
    1. Siddique, T., Nijhawan, D. & Hentati, A. (1996) Neurology 47, S27–S35. - PubMed

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