Mitochondrial Dysfunction in CA1 Hippocampal Neurons of the UBE3A Deficient Mouse Model for Angelman Syndrome

Overview

Journal Neurosci Lett

Specialty Neurology

Date 2009 Jul 1

PMID 19563863

Citations 40

Authors

Hailing Su

Weiwei Fan

Pinar E Coskun

Jouni Vesa

June-Anne Gold

Yong-Hui Jiang

Prasanth Potluri

Vincent Procaccio

Allan Acab

John H Weiss

Douglas C Wallace

Virginia E Kimonis

Affiliations

Soon will be listed here.

Abstract

Angelman syndrome (AS) is a severe neurological disorder caused by a deficiency of ubiquitin protein ligase E3A (UBE3A), but the pathophysiology of the disease remains unknown. We now report that in the brains of AS mice in which the maternal UBE3A allele is mutated (m-) and the paternal allele is potentially inactivated by imprinting (p+) (UBE3A m-\p+), the mitochondria are abnormal and exhibit a partial oxidative phosphorylation (OXPHOS) defect. Electron microscopy of the hippocampal region of the UBE3A m-\p+ mice (n=6) reveals small, dense mitochondria with altered cristae, relative to wild-type littermates (n=6) and reduced synaptic vesicle density. The specific activity of OXPHOS complex III is reduced in whole brain mitochondria in UBE3A m-\p+ (n=5) mice versus wild-type littermates (n=5). Therefore, mitochondrial dysfunction may contribute to the pathophysiology of Angelman syndrome.

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References

Cornford M, Philippart M, Jacobs B, SCHEIBEL A, Vinters H . Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. J Child Neurol. 1994; 9(4):424-31. DOI: 10.1177/088307389400900419. View

Keating D . Mitochondrial dysfunction, oxidative stress, regulation of exocytosis and their relevance to neurodegenerative diseases. J Neurochem. 2007; 104(2):298-305. DOI: 10.1111/j.1471-4159.2007.04997.x. View

Jiang Y, Beaudet A . Human disorders of ubiquitination and proteasomal degradation. Curr Opin Pediatr. 2004; 16(4):419-26. DOI: 10.1097/01.mop.0000133634.79661.cd. View

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View

Trounce I, Kim Y, Jun A, Wallace D . Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol. 1996; 264:484-509. DOI: 10.1016/s0076-6879(96)64044-0. View

Collins C, Wairkar Y, Johnson S, DiAntonio A . Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron. 2006; 51(1):57-69. DOI: 10.1016/j.neuron.2006.05.026. View

Karbowski M, Neutzner A, Youle R . The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol. 2007; 178(1):71-84. PMC: 2064424. DOI: 10.1083/jcb.200611064. View

Feinberg A . Phenotypic plasticity and the epigenetics of human disease. Nature. 2007; 447(7143):433-40. DOI: 10.1038/nature05919. View

Dindot S, Antalffy B, Bhattacharjee M, Beaudet A . The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet. 2007; 17(1):111-8. DOI: 10.1093/hmg/ddm288. View

10.

Weeber E, Jiang Y, Elgersma Y, Varga A, Carrasquillo Y, Brown S . Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci. 2003; 23(7):2634-44. PMC: 6742065. View

11.

Escobar-Henriques M, Westermann B, Langer T . Regulation of mitochondrial fusion by the F-box protein Mdm30 involves proteasome-independent turnover of Fzo1. J Cell Biol. 2006; 173(5):645-50. PMC: 2063881. DOI: 10.1083/jcb.200512079. View

12.

Yaari Y, Beck H . "Epileptic neurons" in temporal lobe epilepsy. Brain Pathol. 2002; 12(2):234-9. PMC: 8095735. View

13.

Jiang Y, Armstrong D, Albrecht U, Atkins C, Noebels J, Eichele G . Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998; 21(4):799-811. DOI: 10.1016/s0896-6273(00)80596-6. View

14.

Kriaucionis S, Paterson A, Curtis J, Guy J, Macleod N, Bird A . Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol. 2006; 26(13):5033-42. PMC: 1489175. DOI: 10.1128/MCB.01665-05. View

15.

Eeg-Olofsson O, Teebi A, Daoud A, Zaki M, Besisso M . Rett syndrome: a mitochondrial disease?. J Child Neurol. 1990; 5(3):210-4. DOI: 10.1177/088307389000500311. View

16.

Neutzner A, Youle R . Instability of the mitofusin Fzo1 regulates mitochondrial morphology during the mating response of the yeast Saccharomyces cerevisiae. J Biol Chem. 2005; 280(19):18598-603. DOI: 10.1074/jbc.M500807200. View

17.

Heck D, Zhao Y, Roy S, Ledoux M, Reiter L . Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. Hum Mol Genet. 2008; 17(14):2181-9. PMC: 2902285. DOI: 10.1093/hmg/ddn117. View

18.

Nakamura N, Hirose S . Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell. 2008; 19(5):1903-11. PMC: 2366858. DOI: 10.1091/mbc.e07-11-1103. View

19.

Albrecht U, Sutcliffe J, Cattanach B, Beechey C, Armstrong D, Eichele G . Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997; 17(1):75-8. DOI: 10.1038/ng0997-75. View

20.

Yashiro K, Riday T, Condon K, Roberts A, Bernardo D, Prakash R . Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci. 2009; 12(6):777-83. PMC: 2741303. DOI: 10.1038/nn.2327. View