QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (41) Citing Articles via Google Scholar Google Scholar Articles by Sörensen, L. Articles by Larsson, N.-G. Search for Related Content PubMed PubMed Citation Articles by Sörensen, L. Articles by Larsson, N.-G.

 Previous Article  |  Next Article 

The Journal of Neuroscience, October 15, 2001, 21(20):8082-8090

Late-Onset Corticohippocampal Neurodepletion Attributable to Catastrophic Failure of Oxidative Phosphorylation in MILON Mice

Lene Sörensen¹, Mats Ekstrand¹, José P. Silva¹, Eva Lindqvist², Baoji Xu³, Pierre Rustin⁴, Lars Olson², and Nils-Göran Larsson¹

¹ Departments of Medical Nutrition and Biosciences, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden, ² Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, S-171 77 Stockholm, Sweden, ³ Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, and ⁴ Unite de Recherches sur les Handicaps Genetiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale U393, Hôpital des Enfants Malades, F-75015 Paris, France

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At ~5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

Key words: mitochondria; respiratory chain; reactive oxygen species; ROS; neurodegeneration; oxidative stress; apoptosis; oxidative phosphorylation; OXPHOS; cre-loxP; Tfam; mitochondrial transcription factor A; MILON; neocortex; hippocampus

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/21208082-09$05.00/0

This article has been cited by other articles:

				E. Dufour, M. Terzioglu, F. H. Sterky, L. Sorensen, D. Galter, L. Olson, J. Wilbertz, and N.-G. Larsson Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration Hum. Mol. Genet., May 15, 2008; 17(10): 1418 - 1426. [Abstract] [Full Text] [PDF]

				G. Hudson, P. Amati-Bonneau, E. L. Blakely, J. D. Stewart, L. He, A. M. Schaefer, P. G. Griffiths, K. Ahlqvist, A. Suomalainen, P. Reynier, et al. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance Brain, February 1, 2008; 131(2): 329 - 337. [Abstract] [Full Text] [PDF]

				K. J. Krishnan, L. C. Greaves, A. K. Reeve, and D. Turnbull The ageing mitochondrial genome Nucleic Acids Res., December 3, 2007; 35(22): 7399 - 7405. [Abstract] [Full Text] [PDF]

				H. Fukui, F. Diaz, S. Garcia, and C. T. Moraes Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease PNAS, August 28, 2007; 104(35): 14163 - 14168. [Abstract] [Full Text] [PDF]

				C. Dell'Agnello, S. Leo, A. Agostino, G. Szabadkai, C. Tiveron, A. Zulian, A. Prelle, P. Roubertoux, R. Rizzuto, and M. Zeviani Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice Hum. Mol. Genet., February 15, 2007; 16(4): 431 - 444. [Abstract] [Full Text] [PDF]

				M. I. Ekstrand, M. Terzioglu, D. Galter, S. Zhu, C. Hofstetter, E. Lindqvist, S. Thams, A. Bergstrand, F. S. Hansson, A. Trifunovic, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons PNAS, January 23, 2007; 104(4): 1325 - 1330. [Abstract] [Full Text] [PDF]

				A. Trifunovic, A. Hansson, A. Wredenberg, A. T. Rovio, E. Dufour, I. Khvorostov, J. N. Spelbrink, R. Wibom, H. T. Jacobs, and N.-G. Larsson From the Cover: Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production PNAS, December 13, 2005; 102(50): 17993 - 17998. [Abstract] [Full Text] [PDF]

				M. P. Bayona-Bafaluy, B. Blits, B. J. Battersby, E. A. Shoubridge, and C. T. Moraes Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease PNAS, October 4, 2005; 102(40): 14392 - 14397. [Abstract] [Full Text] [PDF]

				M. I. Ekstrand, M. Falkenberg, A. Rantanen, C. B. Park, M. Gaspari, K. Hultenby, P. Rustin, C. M. Gustafsson, and N.-G. Larsson Mitochondrial transcription factor A regulates mtDNA copy number in mammals Hum. Mol. Genet., May 1, 2004; 13(9): 935 - 944. [Abstract] [Full Text] [PDF]

				A. Hansson, N. Hance, E. Dufour, A. Rantanen, K. Hultenby, D. A. Clayton, R. Wibom, and N.-G. Larsson A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts PNAS, March 2, 2004; 101(9): 3136 - 3141. [Abstract] [Full Text] [PDF]

				A. Agostino, F. Invernizzi, C. Tiveron, G. Fagiolari, A. Prelle, E. Lamantea, A. Giavazzi, G. Battaglia, L. Tatangelo, V. Tiranti, et al. Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice Hum. Mol. Genet., February 15, 2003; 12(4): 399 - 413. [Abstract] [Full Text] [PDF]

				A. Wredenberg, R. Wibom, H. Wilhelmsson, C. Graff, H. H. Wiener, S. J. Burden, A. Oldfors, H. Westerblad, and N.-G. Larsson Increased mitochondrial mass in mitochondrial myopathy mice PNAS, November 12, 2002; 99(23): 15066 - 15071. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help