title: A computational model of motor neuron degeneration.
abstract: To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations.
authors.affiliation: Neurocentre Magendie, INSERM U862, University of Bordeaux, 33077 Bordeaux, France; Department of Neurology, Neuro-Muscular Unit and ALS Center, CHU de Bordeaux, 33076 Bordeaux, France. Electronic address: gwendal.lemasson@inserm.fr.
authors.forename: Gwendal
authors.initials: G
authors.lastname: Le Masson
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032-3784, USA; Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: sp30@cumc.columbia.edu.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032-3784, USA; Departments of Neuroscience and Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Abbott
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism; D006706:Homeostasis / Q000502:physiology; D008959:Models, Neurological; D009046:Motor Neurons / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D012964:Sodium; D011188:Potassium; D002118:Calcium
references.citation: J Neurol Sci. 1997 Oct;152 Suppl 1:S43-8
references.pmid: 9419053
references.citation: J Mol Cell Cardiol. 2013 Jun;59:205-13
references.pmid: 23538132
references.citation: Muscle Nerve. 1994 Nov;17(11):1243-9
references.pmid: 7935546
references.citation: J Neurosci. 2011 Jun 22;31(25):9093-100
references.pmid: 21697360
references.citation: Biochim Biophys Acta. 1996 Oct 24;1291(2):115-21
references.pmid: 8898871
references.citation: Arch Neurol. 2011 Nov;68(11):1440-6
references.pmid: 22084127
references.citation: J Neurosci Methods. 2000 Nov 30;103(2):145-9
references.pmid: 11084206
references.citation: Adv Exp Med Biol. 2012;740:569-601
references.pmid: 22453961
references.citation: J Neurophysiol. 2012 Feb;107(3):808-23
references.pmid: 22031773
references.citation: Cell Calcium. 2012 Jul;52(1):16-21
references.pmid: 22672876
references.citation: J Physiol Paris. 1999 Jan-Apr;93(1-2):87-96
references.pmid: 10084712
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12329-34
references.pmid: 20616090
references.citation: Cell. 2013 Nov 7;155(4):894-908
references.pmid: 24209626
references.citation: J Neurophysiol. 1993 Apr;69(4):1005-8
references.pmid: 8492143
references.citation: Neuron. 2014 Mar 5;81(5):1001-1008
references.pmid: 24508385
references.citation: J Physiol. 2002 Oct 15;544(2):521-36
references.pmid: 12381824
references.citation: J Comp Neurol. 1984 Dec 1;230(2):231-48
references.pmid: 6210310
references.citation: Neuron. 2012 Sep 6;75(5):762-77
references.pmid: 22958818
references.citation: Cell. 2007 Dec 14;131(6):1047-58
references.pmid: 18083096
references.citation: Lancet Neurol. 2012 Apr;11(4):323-30
references.pmid: 22406228
references.citation: Annu Rev Neurosci. 2010;33:409-40
references.pmid: 20367447
references.citation: Cell. 2014 Feb 13;156(4):825-35
references.pmid: 24529383
references.citation: Biochim Biophys Acta. 2014 Aug;1842(8):1295-301
references.pmid: 24568860
references.citation: Muscle Nerve. 1998 Mar;21(3):336-44
references.pmid: 9486862
references.citation: Neurology. 2008 Jan 29;70(5):353-9
references.pmid: 18227416
references.citation: J Physiol. 1980 Jul;304:251-76
references.pmid: 7441537
references.citation: J Neurosci. 2012 Jun 27;32(26):8940-51
references.pmid: 22745494
references.citation: Nat Rev Neurosci. 2008 Jul;9(7):505-18
references.pmid: 18568013
references.citation: Neuron. 2010 Dec 9;68(5):857-64
references.pmid: 21145000
references.citation: Front Neuroenergetics. 2012 Feb 01;4:2
references.pmid: 22347180
references.citation: Ann Neurol. 1999 Nov;46(5):787-90
references.pmid: 10553999
references.citation: J Comput Neurosci. 1994 Aug;1(3):195-230
references.pmid: 8792231
references.citation: J Neurophysiol. 1962 Nov;25:772-89
references.pmid: 14013544
references.citation: J Comp Neurol. 2005 Mar 14;483(3):304-17
references.pmid: 15682391
references.citation: J Physiol. 2006 Jun 15;573(Pt 3):663-77
references.pmid: 16613880
references.citation: Annu Rev Biophys. 2011;40:243-66
references.pmid: 21351879
references.citation: Ann Neurol. 1982 Dec;12(6):542-7
references.pmid: 7159056
references.citation: N Engl J Med. 2010 Mar 11;362(10):953-4
references.pmid: 20220193
references.citation: Neuron. 2011 Jun 23;70(6):1033-53
references.pmid: 21689593
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20523-8
references.pmid: 21059924
references.citation: Science. 1993 Mar 26;259(5103):1915-7
references.pmid: 8456317
references.citation: Annu Rev Physiol. 1989;51:491-506
references.pmid: 2653192
references.citation: J Neuropathol Exp Neurol. 2007 Jan;66(1):10-6
references.pmid: 17204932
references.citation: Cancer Res. 2014 Feb 15;74(4):1056-66
references.pmid: 24371227
references.citation: Biophys J. 1998 Sep;75(3):1403-9
references.pmid: 9726941
references.citation: PLoS Comput Biol. 2010 Jul 01;6:e1000840
references.pmid: 20617202
references.citation: Neuron. 2013 Apr 10;78(1):57-64
references.pmid: 23498975
references.citation: Nature. 2010 May 13;465(7295):223-6
references.pmid: 20428114
references.citation: J Neurol Neurosurg Psychiatry. 2011 May;82(5):549-51
references.pmid: 20462913
references.citation: J Comp Neurol. 1998 Mar 30;393(1):69-83
references.pmid: 9520102
references.citation: J Exp Biol. 2008 Jun;211(Pt 11):1792-804
references.pmid: 18490395
references.citation: J Neuropathol Exp Neurol. 1984 Sep;43(5):471-80
references.pmid: 6540800
references.citation: Eur J Nucl Med Mol Imaging. 2014 May;41(5):844-52
references.pmid: 24445987
references.citation: Neural Comput. 1997 Aug 15;9(6):1179-209
references.pmid: 9248061
references.citation: Neuron. 2012 Mar 8;73(5):862-85
references.pmid: 22405199
references.citation: J Neurol Sci. 1973 Oct;20(2):199-209
references.pmid: 4750876
references.citation: Neuron. 2013 Oct 2;80(1):80-96
references.pmid: 24094105
references.citation: J Physiol. 1952 Aug;117(4):500-44
references.pmid: 12991237
references.citation: Neuron. 1998 Jul;21(1):13-26
references.pmid: 9697848
references.citation: J Neurophysiol. 2013 Jun;109(11):2803-14
references.pmid: 23486205
references.citation: Neuron. 2013 Dec 4;80(5):1175-89
references.pmid: 24210906
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10479-86
references.pmid: 23759742
references.citation: Science. 2014 Feb 7;343(6171):665-70
references.pmid: 24503854
references.citation: Neurology. 2004 Aug 24;63(4):721-3
references.pmid: 15326252