Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice
dc.contributor.author | Jones, Julie M. | en_US |
dc.contributor.author | Datta, Prasanta | en_US |
dc.contributor.author | Srinivasula, S. M. | en_US |
dc.contributor.author | Ji, Weizhen | en_US |
dc.contributor.author | Gupta, S. | en_US |
dc.contributor.author | Zhang, Z. J. | en_US |
dc.contributor.author | Davies, E. | en_US |
dc.contributor.author | Hajnoczky, G. | en_US |
dc.contributor.author | Saunders, Thomas L. | en_US |
dc.contributor.author | Van Keuren, Margaret L. | en_US |
dc.contributor.author | Fernandes-Alnemri, T. | en_US |
dc.contributor.author | Meisler, Miriam H. | en_US |
dc.contributor.author | Alnemri, E. S. | en_US |
dc.date.accessioned | 2009-06-01T17:23:53Z | |
dc.date.available | 2009-06-01T17:23:53Z | |
dc.date.issued | 2003-10-16 | en_US |
dc.identifier.citation | Jones, JM; Datta, P; Srinivasula, SM; Ji, WZ; Gupta, S; Zhang, ZJ; Davies, E; Hajnoczky, G; Saunders, TL; Van Keuren, ML; Fernandes-Alnemri, T; Meisler, MH; Alnemri, ES. (2003) "Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice." Nature 425(6959): 721-727. <http://hdl.handle.net/2027.42/62561> | en_US |
dc.identifier.issn | 0028-0836 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/62561 | |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=14534547&dopt=citation | en_US |
dc.description.abstract | The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age(1,2). Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages'. Here we have identified the mnd2 mutation as the missense mutation Ser276Cys in the protease domain of the nuclear-encoded mitochondrial serine protease Omi (also known as HtrA2 or Prss25). Protease activity of Omi is greatly reduced in tissues of mnd2 mice but is restored in mice rescued by a bacterial artificial chromosome transgene containing the wildtype Omi gene. Deletion of the PDZ domain partially restores protease activity to the inactive recombinant Omi protein carrying the Ser276Cys mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. The neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease. | en_US |
dc.format.extent | 634499 bytes | |
dc.format.extent | 2489 bytes | |
dc.format.mimetype | application/octet-stream | |
dc.format.mimetype | text/plain | |
dc.publisher | Nature Publishing Group | en_US |
dc.source | Nature | en_US |
dc.title | Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice | en_US |
dc.type | Article | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA | en_US |
dc.contributor.affiliationum | Univ Michigan, Dept Internal Med, Div Med & Mol Genet, Ann Arbor, MI 48109 USA | en_US |
dc.contributor.affiliationum | Univ Michigan, Biomed Res Core Facil, Transgen Anim Model Core, Ann Arbor, MI 48109 USA | en_US |
dc.contributor.affiliationother | Thomas Jefferson Univ Hosp, Ctr Apoptosis Res, Philadelphia, PA 19107 USA | en_US |
dc.contributor.affiliationother | Thomas Jefferson Univ Hosp, Kimmel Canc Inst, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA | en_US |
dc.contributor.affiliationother | Thomas Jefferson Univ Hosp, Dept Pathol & Cell Biol, Philadelphia, PA 19107 USA | en_US |
dc.identifier.pmid | 14534547 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/62561/1/nature02052.pdf | |
dc.identifier.doi | http://dx.doi.org/10.1038/nature02052 | en_US |
dc.identifier.source | Nature | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.