**11. References**


Ca2+ entry, increased motoneuronal size, altered glutamate neurotransmission, astrocyte dysfunction, mitochondrial deficits, failures in axon transport, and problems in protein degradation act in concert and gradually push motoneurons outside the parameters under which they can function properly. The fact that motoneurons are able to remain functioning for as long as they do under adverse conditions suggests that there is a large window of time and intrinsic conditions within which motoneurons can maintain normal function. Hopefully future treatments can target these altered pathways to extend the time

Ackerley S, Grierson AJ, Banner S, Perkinton MS, Brownlees J, Byers HL, Ward M, Thornhill

Ackerley S, Grierson AJ, Brownlees J, Thornhill P, Anderton BH, Leigh PN, Shaw CE, Miller

Alaburda A, Perrier JF, Hounsgaard J (2002) Mechanisms causing plateau potentials in

Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282-1289. Amendola J, Durand J (2008) Morphological differences between wild-type and transgenic

Amendola J, Verrier B, Roubertoux P, Durand J (2004) Altered sensorimotor development in

Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK (2008) Endoplasmic

Bayliss DA, Umemiya M, Berger AJ (1995) Inhibition of N- and P-type calcium currents and

Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH

Bendotti C, Tortarolo M, Suchak SK, Calvaresi N, Carvelli L, Bastone A, Rizzi M, Rattray M,

Bergmann F, Keller BU (2004) Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones from mouse. J Physiol 555:45-59.

amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021-16026. Bellingham MC (2011) A review of the neural mechanisms of action and clinical efficiency of

P, Hussain K, Waby JS, Anderton BH, Cooper JD, Dingwall C, Leigh PN, Shaw CE, Miller CC (2004) p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic

CC (2000) Glutamate slows axonal transport of neurofilaments in transfected

superoxide dismutase 1 lumbar motoneurons in postnatal mice. J Comp Neurol

a transgenic mouse model of amyotrophic lateral sclerosis. Eur J Neurosci 20:2822-

reticulum stress and induction of the unfolded protein response in human sporadic

the after-hyperpolarization in rat motoneurones by serotonin. Journal of

(2006) Wild-type microglia extend survival in PU.1 knockout mice with familial

riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last

Mennini T (2001) Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem

motoneuron properties remain within these parameters.

lateral sclerosis. Mol Cell Neurosci 26:354-364.

spinal motoneurones. Adv Exp Med Biol 508:219-226.

amyotrophic lateral sclerosis. Neurobiol Dis 30:400-407.

neurons. J Cell Biol 150:165-176.

511:329-341.

79:737-746.

Physiology 485:635-647.

decade? CNS Neurosci Ther 17:4-31.

2826.

**11. References** 


Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis 187

Heckman CJ, Johnson M, Mottram C, Schuster J (2008b) Persistent inward currents in spinal

Heckman CJ, Kuo JJ, Johnson MD (2004) Synaptic integration in motoneurons with hyper-

Hegedus J, Putman CT, Gordon T (2007) Time course of preferential motor unit loss in the

Hegedus J, Putman CT, Tyreman N, Gordon T (2008) Preferential motor unit loss in the

Hiruma H, Katakura T, Takahashi S, Ichikawa T, Kawakami T (2003) Glutamate and

Hounsgaard J, Kiehn O (1989) Serotonin-induced bistability of turtle motoneurones caused by a nifedipine-sensitive calcium plateau potential. J Physiol Lond 414:265-282. Hsiao CF, Del Negro CA, Trueblood PR, Chandler SH (1998) Ionic basis for serotonin-

Hultborn H, Brownstone RB, Toth TI, Gossard JP (2004) Key mechanisms for setting the input-output gain across the motoneuron pool. Prog Brain Res 143:77-95. Ignacio S, Moore DH, Smith AP, Lee NM (2005) Effect of neuroprotective drugs on gene

Ilieva EV, Ayala V, Jove M, Dalfo E, Cacabelos D, Povedano M, Bellmunt MJ, Ferrer I,

Israelson A, Arbel N, Da Cruz S, Ilieva H, Yamanaka K, Shoshan-Barmatz V, Cleveland DW

Ito Y, Yamada M, Tanaka H, Aida K, Tsuruma K, Shimazawa M, Hozumi I, Inuzuka T,

Jahn K, Grosskreutz J, Haastert K, Ziegler E, Schlesinger F, Grothe C, Dengler R, Bufler J

interplay in sporadic amyotrophic lateral sclerosis. Brain 130:3111-3123. Ilieva HS, Yamanaka K, Malkmus S, Kakinohana O, Yaksh T, Marsala M, Cleveland DW

expression in G93A/SOD1 mice. Ann N Y Acad Sci 1053:121-136.

hippocampal neurons by different mechanisms. J Neurosci 23:8967-8977. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O (1988) Bistability of alpha-motoneurones in

Neuroscientist 14:264-275.

hydroxytryptophan. J Physiol 405:345-367.

model of inherited ALS. Neuron 67:575-587.

Neurophysiol 79:2847-2856.

U S A 105:12599-12604.

Neuroscience 142:1019-1029.

476.

164.

586:3337-3351.

motoneurons and their influence on human motoneuron firing patterns.

excitable dendrites. Canadian journal of physiology and pharmacology 82:549-555.

SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 28:154-

SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol

amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat

the decerebrate cat and in the acute spinal cat after intravenous 5-

induced bistable membrane properties in guinea pig trigeminal motoneurons. J

Pamplona R, Portero-Otin M (2007) Oxidative and endoplasmic reticulum stress

(2008) Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death. Proc Natl Acad Sci

(2010) Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse

Takahashi H, Hara H (2009) Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. Neurobiol Dis 36:470-

(2006) Temporospatial coupling of networked synaptic activation of AMPA-type glutamate receptor channels and calcium transients in cultured motoneurons.


Dal Canto MC, Gurney ME (1994) Development of central nervous system pathology in a

Dal Canto MC, Gurney ME (1995) Neuropathological changes in two lines of mice carrying

Damiano M, Starkov AA, Petri S, Kipiani K, Kiaei M, Mattiazzi M, Flint Beal M, Manfredi G

De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau KF, Brownlees J, Ackerley

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y,

Elbasiouny SM, Amendola J, Durand J, Heckman CJ (2010) Evidence from computer

Fierro L, Llano I (1996) High endogenous calcium buffering in Purkinje cells from rat

Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak

Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of

Gonzalez-Islas C, Wenner P (2006) Spontaneous network activity in the embryonic spinal cord regulates AMPAergic and GABAergic synaptic strength. Neuron 49:563-575. Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, Billiau AD,

Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J,

neurodegenerative diseases. Annu Rev Neurosci 31:151-173.

adult-onset ALS and ALS/dementia. Nature.

cerebellar slices. J Physiol 496 ( Pt 3):617-625.

in mice and man. Exp Neurol 185:232-240.

superoxide dismutase. J Neurosci 28:10234-10244.

diseases. J Neurosci 20:2534-2542.

journal of pathology 145:1271-1279.

676:25-40.

96:1349-1361.

Neurosci In Press.

1775.

murine transgenic model of human amyotrophic lateral sclerosis. The American

a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res

(2006) Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J Neurochem

S, Shaw PJ, McLoughlin DM, Shaw CE, Leigh PN, Miller CC, Grierson AJ (2007) Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet 16:2720-2728. De Vos KJ, Grierson AJ, Ackerley S, Miller CC (2008) Role of axonal transport in

Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and

simulations for alterations in the membrane biophysical properties and dendritic processing of synaptic inputs in mutant superoxide dismutase-1 motoneurons. J

MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence

neuromuscular synapse subtypes with low sprouting competence in motoneuron

Robberecht W, Julien JP (2008) Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant

Hentati A, Kwon YW, Deng HX, et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772-


Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis 189

Lauriat TL, Richler E, McInnes LA (2007) A quantitative regional expression profile of

Lee CH, Inoki K, Guan KL (2007) mTOR pathway as a target in tissue hypertrophy. Annual

Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces

Lee RH, Heckman CJ (1999) Enhancement of bistability in spinal motoneurons in vivo by the

Li Q, Vande Velde C, Israelson A, Xie J, Bailey AO, Dong MQ, Chun SJ, Roy T, Winer L,

Li Y, Li X, Harvey PJ, Bennett DJ (2004) Effects of baclofen on spinal reflexes and persistent

Lim PJ, Danner R, Liang J, Doong H, Harman C, Srinivasan D, Rothenberg C, Wang H, Ye Y,

Lips MB, Keller BU (1998) Endogenous calcium buffering in motoneurones of the nucleus

Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538-542. MacAskill AF, Atkin TA, Kittler JT (2010) Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. Eur J Neurosci 32:231-240. Macaskill AF, Rinholm JE, Twelvetrees AE, Arancibia-Carcamo IL, Muir J, Fransson A,

Maragakis NJ, Dykes-Hoberg M, Rothstein JD (2004) Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol 55:469-477. Marder E, Rehm KJ (2005) Development of central pattern generating circuits. Curr Opin

Marks JD, Donnelly DF, Haddad GG (1993) Adenosine-induced inhibition of vagal

Mattiazzi M, D'Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G

Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and

motoneuron excitability: receptor subtype and mechanisms. Am J Physiol 264:L124-

(2002) Mutated human SOD1 causes dysfunction of oxidative phosphorylation in

sclerosis and frontotemporal dementia. Lancet Neurol 9:995-1007.

mitochondria of transgenic mice. J Biol Chem 277:29626-29633.

neurological disorders. Neuron 60:748-766.

decreases protein import. Proc Natl Acad Sci U S A 107:21146-21151. Li X, Murray K, Harvey PJ, Ballou EW, Bennett DJ (2007) Serotonin facilitates a persistent

splicing in disease. Neurochemistry international 50:271-280.

review of pharmacology and toxicology 47:443-467.

injury. J Neurophysiol 97:1236-1246.

involved in ERAD. J Cell Biol 187:201-217.

hypoglossus from mouse. J Physiol 511 ( Pt 1):105-117.

Neurophysiol 92:2694-2703.

Neurobiol 15:86-93.

132.

2174.

cleavage of p35 to p25 by calpain. Nature 405:360-364.

EAAT2 known and novel splice variants reopens the question of aberrant EAAT2

noradrenergic alpha1 agonist methoxamine. Journal of neurophysiology 81:2164-

Yates JR, Capaldi RA, Cleveland DW, Miller TM (2010) ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and

calcium current in motoneurons of rats with and without chronic spinal cord

inward currents in motoneurons of chronic spinal rats with spasticity. J

Fang S, Monteiro MJ (2009) Ubiquilin and p97/VCP bind erasin, forming a complex

Aspenstrom P, Attwell D, Kittler JT (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61:541-555. Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral


Jaiswal MK, Keller BU (2009) Cu/Zn superoxide dismutase typical for familial amyotrophic

Jaiswal MK, Zech WD, Goos M, Leutbecher C, Ferri A, Zippelius A, Carri MT, Nau R, Keller

Jiang M, Schuster JE, Fu R, Siddique T, Heckman CJ (2009) Progressive changes in synaptic

Jiang Z, Rempel J, Li J, Sawchuk MA, Carlin KP, Brownstone RM (1999) Development of L-

Johnston JA, Dalton MJ, Gurney ME, Kopito RR (2000) Formation of high molecular weight

Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S (2004) Glutamate receptors:

Kawahara Y, Sun H, Ito K, Hideyama T, Aoki M, Sobue G, Tsuji S, Kwak S (2006)

Kawasaki H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y, Nishida E (1997)

Kieran D, Hafezparast M, Bohnert S, Dick JR, Martin J, Schiavo G, Fisher EM, Greensmith L

Kim TY, Kim E, Yoon SK, Yoon JB (2008) Herp enhances ER-associated protein degradation by recruiting ubiquilins. Biochem Biophys Res Commun 369:741-746. Kuo JJ, Siddique T, Fu R, Heckman CJ (2005) Increased persistent Na+ current and its effect

Kwak S, Kawahara Y (2005) Deficient RNA editing of GluR2 and neuronal death in

Ladewig T, Lalley PM, Keller BU (2004) Serotonergic modulation of intracellular calcium dynamics in neonatal hypoglossal motoneurons from mouse. Brain Res 1001:1-12. Landmesser LT, O'Donovan MJ (1984) Activation patterns of embryonic chick hind limb

amyotropic lateral sclerosis. J Mol Med (Berl) 83:110-120.

RNA editing and death of motor neurons. Nature 427:801.

amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 97:12571-12576. Kaiser M, Maletzki I, Hulsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F, Bahr M,

homeostasis in SOD1G93A mice. Mol Pharmacol 75:478-489.

model of motoneuron disease. BMC Neurosci 10:64.

lateral sclerosis. J Neurosci 29:15031-15038.

sclerosis. J Neurochem 99:900-912.

Neuroreport 7:1427-1431.

span of ALS mice. J Cell Biol 169:561-567.

Physiology-London 563:843-854.

54:11-14.

347:189-204.

mouse spinal cord. Eur J Neurosci 11:3481-3487.

lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+

BU (2009) Impairment of mitochondrial calcium handling in a mtSOD1 cell culture

inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic

type calcium channels and a nifedipine-sensitive motor activity in the postnatal

complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial

Neusch C (2006) Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the SOD1 (G93A) transgenic mouse model of amyotrophic lateral

Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA. Neurosci Res

Activation and involvement of p38 mitogen-activated protein kinase in glutamateinduced apoptosis in rat cerebellar granule cells. J Biol Chem 272:18518-18521. Kennel PF, Finiels F, Revah F, Mallet J (1996) Neuromuscular function impairment is not

caused by motor neurone loss in FALS mice: an electromyographic study.

(2005) A mutation in dynein rescues axonal transport defects and extends the life

on excitability in motoneurones cultured from mutant SOD1 mice. Journal of

muscles recorded in ovo and in an isolated spinal cord preparation. J Physiol


Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis 191

Pieri M, Carunchio I, Curcio L, Mercuri NB, Zona C (2009) Increased persistent sodium

Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and

Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun

Powers RK, Binder MD (2001) Input-output functions of mammalian motoneurons. Rev

Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of

Quinlan KA, Schuster JE, Fu R, Siddique T, Heckman CJ (2011) Altered postnatal maturation

Raoul C, Estevez AG, Nishimune H, Cleveland DW, deLapeyriere O, Henderson CE, Haase

Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood

Ren K, Ruda MA (1994) A comparative study of the calcium-binding proteins calbindin-

Rintoul GL, Bennett VJ, Papaconstandinou NA, Reynolds IJ (2006) Nitric oxide inhibits

Rintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ (2003) Glutamate decreases

Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J,

are associated with familial amyotrophic lateral sclerosis. Nature 362:59-62. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464-1468. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg

mitochondrial membrane potential. J Neurochem 97:800-806.

lateral sclerosis. Exp Neurol 215:368-379.

Physiol Biochem Pharmacol 143:137-263.

lateral sclerosis. J Physiol 589:2245-2260.

death after axonal injury. Nat Genet 13:43-47.

response. Nat Rev Mol Cell Biol 8:519-529.

expression. Nature 433:73-77.

Brain Res Rev 19:163-179.

23:7881-7888.

14:459-468.

9:408-419.

1083.

dysfunction in neurons. The FEBS journal 277:3622-3636.

current determines cortical hyperexcitability in a genetic model of amyotrophic

E, Wancewicz E, Mazur C, Kordasiewicz H, Sedaghat Y, Donohue JP, Shiue L, Bennett CF, Yeo GW, Cleveland DW (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci

phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci

of electrical properties in spinal motoneurons in a mouse model of amyotrophic

G, Pettmann B (2002) Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. Neuron 35:1067-

DG, Beal MF, Brown RH, Jr., Scott RW, Snider WD (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell

D28K, calretinin, calmodulin and parvalbumin in the rat spinal cord. Brain Res

mitochondrial movement in forebrain neurons associated with disruption of

mitochondrial size and movement in primary forebrain neurons. J Neurosci

O'Regan JP, Deng HX, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene

M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter


McCue HV, Haynes LP, Burgoyne RD (2010) The diversity of calcium sensor proteins in the regulation of neuronal function. Cold Spring Harb Perspect Biol 2:a004085. Meehan CF, Moldovan M, Marklund SL, Graffmo KS, Nielsen JB, Hultborn H (2010)

Mironov SL (2007) ADP regulates movements of mitochondria in neurons. Biophys J

Moreno-Lopez B, Sunico CR, Gonzalez-Forero D (2011) NO orchestrates the loss of synaptic

Mourelatos Z, Gonatas NK, Stieber A, Gurney ME, Dal Canto MC (1996) The Golgi

Munch C, Ebstein M, Seefried U, Zhu B, Stamm S, Landwehrmeyer GB, Ludolph AC,

Mynlieff M, Beam KG (1994) Adenosine acting at an A1 receptor decreases N-type calcium

Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007)

Neher E (1995) The use of fura-2 for estimating Ca buffers and Ca fluxes.

Nguyen KT, Garcia-Chacon LE, Barrett JN, Barrett EF, David G (2009) The Psi(m)

Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F,

Pardo CA, Xu Z, Borchelt DR, Price DL, Sisodia SS, Cleveland DW (1995) Superoxide

Perrier JF, Delgado-Lezama R (2005) Synaptic release of serotonin induced by stimulation of

Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of

glial activation in motor neuron disease. Lancet Neurol 10:253-263.

inward currents. Acta Physiol (Oxf) 200:361-376.

disease. Proc Natl Acad Sci U S A 93:5472-5477.

motor neurons. Nat Neurosci 10:615-622.

the mouse spinal cord. J Physiol 520 Pt 2:485-502.

degenerative diseases of the brain. Cell calcium 34:365-383.

Neuropharmacology 34:1423-1442.

turtle. J Neurosci 25:7993-7999.

amyotrophic lateral sclerosis. J Neurochem 82:594-603.

current in mouse motoneurons. J Neurosci 14:3628-3634.

92:2944-2952.

2011.

Neurobiol 43:41-66.

Intrinsic properties of lumbar motor neurones in the adult G127insTGGG superoxide dismutase-1 mutant mouse in vivo: evidence for increased persistent

boutons from adult "sick" motoneurons: modeling a molecular mechanism. Mol

apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the

Schwalenstocker B, Meyer T (2002) Alternative splicing of the 5'-sequences of the mouse EAAT2 glutamate transporter and expression in a transgenic model for

Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to

depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals. Proc Natl Acad Sci U S A 106:2007-

Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. American journal of human genetics 75:822-831. Palecek J, Lips MB, Keller BU (1999) Calcium dynamics and buffering in motoneurones of

dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci U S A 92:954-958. Paschen W (2003) Endoplasmic reticulum: a primary target in various acute disorders and

the raphe nucleus promotes plateau potentials in spinal motoneurons of the adult


Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis 193

Van Den Bosch L (2011) Genetic rodent models of amyotrophic lateral sclerosis. Journal of

van Zundert B, Peuscher MH, Hynynen M, Chen A, Neve RL, Brown RH, Jr., Constantine-

Vanselow BK, Keller BU (2000) Calcium dynamics and buffering in oculomotor neurones

Vinay L, Brocard F, Pflieger JF, Simeoni-Alias J, Clarac F (2000) Perinatal development of

von Lewinski F, Fuchs J, Vanselow BK, Keller BU (2008) Low Ca2+ buffering in hypoglossal motoneurons of mutant SOD1 (G93A) mice. Neurosci Lett 445:224-228. von Lewinski F, Keller BU (2005) Mitochondrial Ca2+ buffering in hypoglossal motoneurons

Wagner OI, Lifshitz J, Janmey PA, Linden M, McIntosh TK, Leterrier JF (2003) Mechanisms of mitochondria-neurofilament interactions. J Neurosci 23:9046-9058. Wang L, Sharma K, Grisotti G, Roos RP (2009) The effect of mutant SOD1 dismutase activity

Warita H, Itoyama Y, Abe K (1999) Selective impairment of fast anterograde axonal

Warita H, Manabe Y, Murakami T, Shiote M, Shiro Y, Hayashi T, Nagano I, Shoji M, Abe K

Williamson TL, Cleveland DW (1999) Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2:50-56. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS,

Xu W, Lipscombe D (2001) Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively

Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi

mice with ALS-linked mutant SOD1. Neurological research 24:577-581. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D,

Acad Sci U S A 104:14825-14830.

biomedicine & biotechnology 2011:348765.

from mouse. Neurosci Lett 380:203-208.

mutant SOD1 gene. Brain Res 819:120-131.

Neurobiol Dis 35:234-240.

chemical biology 4:295-305.

822.

mitochondria. Neuron 14:1105-1116.

dihydropyridines. J Neurosci 21:5944-5951.

amyotrophic lateral sclerosis. J Neurosci 28:10864-10874.

(ALS)-related motoneurone disease. J Physiol 525 Pt 2:433-445.

expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl

Paton M, Bellingham MC (2008) Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease

from mouse that are particularly resistant during amyotrophic lateral sclerosis

lumbar motoneurons and their inputs in the rat. Brain research bulletin 53:635-647.

on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis.

transport in the peripheral nerves of asymptomatic transgenic mice with a G93A

(2002) Tardive decrease of astrocytic glutamate transporter protein in transgenic

Goldsmith P, O'Kane CJ, Floto RA, Rubinsztein DC (2008) Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature

Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of

hyperpolarized membrane potentials and are incompletely inhibited by

R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251-253. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814-


Sasaki S, Warita H, Abe K, Komori T, Iwata M (2001) EAAT1 and EAAT2 immunoreactivity in transgenic mice with a G93A mutant SOD1 gene. Neuroreport 12:1359-1362. Saxena S, Cabuy E, Caroni P (2009) A role for motoneuron subtype-selective ER stress in

Scamps F, Roig A, Boukhaddaoui H, Andre S, Puech S, Valmier J (2004) Activation of P-type

Schwarzschild MA, Cole RL, Hyman SE (1997) Glutamate, but not dopamine, stimulates

Steinbeck JA, Henke N, Opatz J, Gruszczynska-Biegala J, Schneider L, Theiss S, Hamacher

Stevenson A, Yates DM, Manser C, De Vos KJ, Vagnoni A, Leigh PN, McLoughlin DM,

Sukiasyan N, Hultborn H, Zhang M (2009) Distribution of calcium channel Ca(V)1.3

Sun H, Kawahara Y, Ito K, Kanazawa I, Kwak S (2006) Slow and selective death of spinal

Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J, Julien JP (2011)

Tortarolo M, Grignaschi G, Calvaresi N, Zennaro E, Spaltro G, Colovic M, Fracasso C, Guiso

Tortarolo M, Veglianese P, Calvaresi N, Botturi A, Rossi C, Giorgini A, Migheli A, Bendotti

Turner BJ, Lopes EC, Cheema SS (2003a) Neuromuscular accumulation of mutant

Turner BJ, Rembach A, Spark R, Lopes EC, Cheema SS (2003b) Opposing effects of low and

Van Damme P, Bogaert E, Dewil M, Hersmus N, Kiraly D, Scheveneels W, Bockx I, Braeken

amytrophic lateral sclerosis-like disease. J Neurosci Res 83:134-146.

amyotrophic lateral sclerosis. Neurosci Lett 350:132-136.

calcium channel regulates a unique thapsigargin-sensitive calcium pool in

stress-activated protein kinase and AP-1-mediated transcription in striatal neurons.

N, Steinfarz B, Golz S, Brustle O, Kuznicki J, Methner A (2011) Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy.

Miller CC (2009) Riluzole protects against glutamate-induced slowing of

immunoreactivity in the rat spinal cord and brain stem. Neuroscience 159:217-

motor neurons in vivo by intrathecal infusion of kainic acid: implications for AMPA receptor-mediated excitotoxicity in ALS. Journal of neurochemistry 98:782-

Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.

G, Elger B, Schneider H, Seilheimer B, Caccia S, Bendotti C (2006) Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of

C (2003) Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression.

superoxide dismutase 1 aggregates in a transgenic mouse model of familial

high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. J

D, Verpoorten N, Verhoeven K, Timmerman V, Herijgers P, Callewaert G, Carmeliet P, Van Den Bosch L, Robberecht W (2007) Astrocytes regulate GluR2

disease manifestations of FALS mice. Nat Neurosci 12:627-636.

embryonic motoneurons. Eur J Neurosci 19:977-982.

neurofilament axonal transport. Neurosci Lett 454:161-164.

J Neurosci 17:3455-3466.

Exp Neurol.

235.

791.

Brain.

Mol Cell Neurosci 23:180-192.

Neurosci Res 74:605-613.

expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci U S A 104:14825-14830.


**Part 2** 

**Signalling Pathways and** 

**Molecular Pathophysiology** 

