Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells. (original) (raw)

• Journal List
• Proc Natl Acad Sci U S A
• v.92(7); 1995 Mar 28
• PMC42351

Proc Natl Acad Sci U S A. 1995 Mar 28; 92(7): 3024–3028.

Abstract

Familial amyotrophic lateral sclerosis (FALS) is associated with mutations in SOD1, the gene encoding copper/zinc superoxide dismutase (CuZnSOD). However, the mechanism by which these mutations lead to amyotrophic lateral sclerosis is unknown. We report that FALS mutant SODs expressed in yeast lacking CuZnSOD are enzymatically active and restore the yeast to the wild-type phenotype. In mammalian neural cells, the overexpression of wild-type SOD1 inhibits apoptosis induced by serum and growth factor withdrawal or calcium ionophore. In contrast, FALS-associated SOD1 mutants promote, rather than inhibit, neural apoptosis, in a dominant fashion, despite the fact that these mutants retain enzymatic SOD activity both in yeast and in mammalian neural cells. The results dissociate the SOD activity of FALS-associated mutants from the induction of neural cell death, suggesting that FALS associated with mutations in SOD1 may not be simply the result of a decrease in the enzymatic function of CuZnSOD. Furthermore, the results provide an in vitro model that may help to define the mechanism by which FALS-associated SOD1 mutations lead to neural cell death.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

• Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. [PubMed] [Google Scholar]
• Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 1993 Aug 20;261(5124):1047–1051. [PubMed] [Google Scholar]
• Bowling AC, Schulz JB, Brown RH, Jr, Beal MF. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1993 Dec;61(6):2322–2325. [PubMed] [Google Scholar]
• Robberecht W, Sapp P, Viaene MK, Rosen D, McKenna-Yasek D, Haines J, Horvitz R, Theys P, Brown R., Jr Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1994 Jan;62(1):384–387. [PubMed] [Google Scholar]
• Aoki M, Ogasawara M, Matsubara Y, Narisawa K, Nakamura S, Itoyama Y, Abe K. Mild ALS in Japan associated with novel SOD mutation. Nat Genet. 1993 Dec;5(4):323–324. [PubMed] [Google Scholar]
• Park EC, Horvitz HR. Mutations with dominant effects on the behavior and morphology of the nematode Caenorhabditis elegans. Genetics. 1986 Aug;113(4):821–852. [PMC free article] [PubMed] [Google Scholar]
• Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, Wong PC, Brown RH, Jr, Price DL, Sisodia SS, Cleveland DW. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8292–8296. [PMC free article] [PubMed] [Google Scholar]
• Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994 Jun 17;264(5166):1772–1775. [PubMed] [Google Scholar]
• Hill JE, Myers AM, Koerner TJ, Tzagoloff A. Yeast/E. coli shuttle vectors with multiple unique restriction sites. Yeast. 1986 Sep;2(3):163–167. [PubMed] [Google Scholar]
• Heikkila RE, Cabbat F. A sensitive assay for superoxide dismutase based on the autoxidation of 6-hydroxydopamine. Anal Biochem. 1976 Oct;75(2):356–362. [PubMed] [Google Scholar]
• Zhong LT, Sarafian T, Kane DJ, Charles AC, Mah SP, Edwards RH, Bredesen DE. bcl-2 inhibits death of central neural cells induced by multiple agents. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4533–4537. [PMC free article] [PubMed] [Google Scholar]
• Levanon D, Lieman-Hurwitz J, Dafni N, Wigderson M, Sherman L, Bernstein Y, Laver-Rudich Z, Danciger E, Stein O, Groner Y. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J. 1985 Jan;4(1):77–84. [PMC free article] [PubMed] [Google Scholar]
• Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. [PMC free article] [PubMed] [Google Scholar]
• Rabizadeh S, Oh J, Zhong LT, Yang J, Bitler CM, Butcher LL, Bredesen DE. Induction of apoptosis by the low-affinity NGF receptor. Science. 1993 Jul 16;261(5119):345–348. [PubMed] [Google Scholar]
• Rabizadeh S, LaCount DJ, Friesen PD, Bredesen DE. Expression of the baculovirus p35 gene inhibits mammalian neural cell death. J Neurochem. 1993 Dec;61(6):2318–2321. [PubMed] [Google Scholar]
• Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen DE. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. [PubMed] [Google Scholar]
• Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. [PubMed] [Google Scholar]
• Bermingham-McDonogh O, Gralla EB, Valentine JS. The copper, zinc-superoxide dismutase gene of Saccharomyces cerevisiae: cloning, sequencing, and biological activity. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4789–4793. [PMC free article] [PubMed] [Google Scholar]
• Sarafian TA, Bredesen DE. Is apoptosis mediated by reactive oxygen species? Free Radic Res. 1994 Jul;21(1):1–8. [PubMed] [Google Scholar]
• Yim MB, Chock PB, Stadtman ER. Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5006–5010. [PMC free article] [PubMed] [Google Scholar]
• Yim MB, Chock PB, Stadtman ER. Enzyme function of copper, zinc superoxide dismutase as a free radical generator. J Biol Chem. 1993 Feb 25;268(6):4099–4105. [PubMed] [Google Scholar]
• Nishida CR, Gralla EB, Valentine JS. Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9906–9910. [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences