Designed to speed transport and communication, bridges may also be useful for slowing disease. Peter Lansbury and Soumya Ray of Brigham and Women’s Hospital, Boston, suggest as much in this week’s early online PNAS in their review of one promising strategy for slowing the progression of ALS.
A small percentage of ALS cases are inherited as autosomal-dominant mutations in the copper/zinc superoxide dismutase gene (SOD1). In these patients, SOD1 accumulates as insoluble aggregates, which have been implicated in the demise of motor neurons (see ARF related news story and ARF related story). Evidence has grown that these ALS mutations also prevent the normal dimerization of SOD. Could this be a clue to treatment? Indeed, it may, suggest Ray and Lansbury.
First the evidence: Recently, Samar Hasnain and colleagues at the Daresbury Laboratory, Cheshire, U.K., showed by x-ray crystallography that one of the most toxic SOD mutants, namely, the one with an alanine-to-valine substitution at amino acid number 4, is twisted into a slightly different shape than normal SOD. This structural deformity, Hasnain and colleagues demonstrated, prevents the monomers from associating as dimers and frees them to enter into more sinister liaisons (see Hough et al., 2004). Couple this with current results from Lansbury’s own lab (in press at Biochemistry), which revealed that covalently dimerizing this same mutant abolishes its tendency to aggregate, and you might just have the makings of a treatment. Lansbury and colleagues dimerized the protein by introducing a disulfide bridge. “A drug-like molecule that stabilizes the SOD1 dimer could inhibit the formation of all the potentially pathogenic species [and] could delay the onset and slow the progress of familial ALS,” the authors write.
The same strategy may also work for sporadic ALS, Ray and Lansbury suggest, because pathogenesis in those cases may be initiated by a variety of complex factors that dissociate the wild-type dimer.—Tom Fagan.
Ray SS, Lansbury Jr PT. A possible therapeutic target for Lou Gehrig’s disease. PNAS 2004. April 20;101:5701-4702.
- Disputing the Dismuting—What Is the Real Role of SOD in ALS?
- ALS—Could Stability Rather than Activity of SOD Hold the Key?
- Hough MA, Grossmann JG, Antonyuk SV, Strange RW, Doucette PA, Rodriguez JA, Whitson LJ, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS. Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5976-81. PubMed.
- Ray SS, Nowak RJ, Strokovich K, Brown RH, Walz T, Lansbury PT. An intersubunit disulfide bond prevents in vitro aggregation of a superoxide dismutase-1 mutant linked to familial amytrophic lateral sclerosis. Biochemistry. 2004 May 4;43(17):4899-905. PubMed.