Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation

  • Manoj Jaiswal
Keywords: Amyotrophic lateral sclerosis (ALS, Motoneuron, Calcium dysregulation, Mitochondria, ER-mitochondria calcium cycle (ERMCC), Selective vulnerability, Calcium buffering, Multifactorial disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex with signature hallmarks of mitochondrial Ca2+ overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium, and in particular low cytosolic calcium ([Ca2+]c) buffering and a strong interaction between metabolic mechanisms and [Ca2+]i have been identified predominantly in motoneuron impairment, the causes of these disruptions are unknown. The existing evidence suggests that the mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS acts through mitochondria, and that alteration in cytosolic and mitochondria-ER microdomain calcium accumulation are critical to the neurodegenerative process. Furthermore, chronic excitotoxcity mediated by Ca2+-permeable AMPA and NMDA receptors seems to initiate vicious cycle of intracellular calcium dysregulation which leads to toxic Ca2+ overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals with high spatiotemporal precision has allowed investigations of calcium regulation in-vivo and in-vitro in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This review provides an overview of latest advances in this field, and focuses on details of what has been learned about disrupted Ca2+ homeostasis and mitochondrial degeneration. It further emphasizes the critical role of mitochondria in preventing apoptosis by acting as a Ca2+ buffers, especially in motoneurons, in pathophysiological conditions such as ALS.

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References

Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med. 2001, 344: 1688-1700.

PubMedGoogle Scholar

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, O’Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung WY, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993, 362 (6415): 59-62.

PubMedGoogle Scholar

Hand CK, Khoris J, Salachas F, Gros-Louis F, Lopes AAS, Mayeux-Portas V, Brown RH, Meininge V, Camu W, Rouleau GA: A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am J Hum Genet. 2002, 70 (1): 251-256.

PubMedCentralPubMedGoogle Scholar

Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR: Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet. 1998, 62 (3): 633-640.

PubMedCentralPubMedGoogle Scholar

Kwiatkowski TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009, 323 (5918): 1205-1208.

PubMedGoogle Scholar

Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y: Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010, 75 (9): 807-814.

PubMedCentralPubMedGoogle Scholar

Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, Gorenstein J, Huang M, Sailer W, Scheffler M, Valesky M, Haines JL, Pericak-Vance M, Siddique T, Horvitz HR, Brown RH: Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet. 2003, 73 (2): 397-403.

PubMedCentralPubMedGoogle Scholar

Nishimura AL, Mitne-Neto M, Silva HC, Oliveira JR, Vainzof M, Zatz M: A novel locus for late onset amyotrophic lateral sclerosis/motor neuron disease variant at 20q13. J Med Genet. 2004, 41 (4): 315-320.

PubMedCentralPubMedGoogle Scholar

Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH, Hardiman O: ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet. 2006, 38 (4): 411-413.

PubMedGoogle Scholar

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008, 319 (5870): 1668-1672.

PubMedGoogle Scholar

Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L: Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 2008, 4: e1000193-

PubMedCentralPubMedGoogle Scholar

Conforti FL, Sproviero W, Simone IL, Mazzei R, Valentino P, Ungaro C, Magariello A, Patitucci A, La Bella V, Sprovieri T, Tedeschi G, Citrigno L, Gabriele AL, Bono F, Monsurrò MR, Muglia M, Gambardella A, Quattrone A: TARDBP gene mutations in south Italian patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2011, 82: 587-588.

PubMedGoogle Scholar

Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH: Deleterious variants of figure four, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009, 84 (1): 85-88.

PubMedCentralPubMedGoogle Scholar

Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN: Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet. 1999, 8 (2): 157-164.

PubMedGoogle Scholar

Mitchell J, Paul P, Chen HJ, Morris A, Payling M, Falchi M, Habgood J, Panoutsou S, Winkler S, Tisato V, Hajitou A, Smith B, Vance C, Shaw C, Mazarakis ND, de Belleroche J: Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc Natl Acad Sci U S A. 2010, 107 (16): 7556-7561.

PubMedCentralPubMedGoogle Scholar

Figlewicz DA, Orrell RW: The genetics of motor neuron diseases. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003, 4 (4): 225-231.

PubMedGoogle Scholar

Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J, Hung WY, McKenna-Yasek D, Haines JL, Pericak-Vance MA, Horvitz HR, Brown RH: Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA. 2000, 284 (13): 1664-1669.

PubMedGoogle Scholar

Suzuki N, Maroof AM, Merkle FT, Koszka K, Intoh A, Armstrong I, Moccia R, Davis-Dusenbery BN, Eggan K: The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci. 2013, 16 (12): 1725-1727.

PubMedCentralPubMedGoogle Scholar

Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, Halloran MA, Gleeson P, Blair IP, Soo KY, King AE, Atkin JD: C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014, Feb 18. [Epub ahead of print]

Google Scholar

Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, Boespflug-Tanguy O: Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002, 71 (3): 518-527.

PubMedCentralPubMedGoogle Scholar

Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, Rimmler J, Hung W, Schlotter B, Ahmed A, Ben Hamida M, Hentati F, Siddique T: Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics. 1998, 2 (1): 55-60.

PubMedGoogle Scholar

Alexianu ME, Ho BK, Mohamed AH, La Bella V, Smith RG, Appel SH: The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol. 1994, 36: 846-858.

PubMedGoogle Scholar

Jaiswal MK, Keller BU: Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+ homeostasis in SOD1G93A mice. Mol Pharmacol. 2009, 75: 478-489.

PubMedGoogle Scholar

Lips MB, Keller BU: Endogenous calcium buffering in motoneurones of the nucleus hypoglossus from mouse. J Physiol. 1998, 511: 105-117.

PubMedCentralPubMedGoogle Scholar

Van Den Bosch L, Schwaller B, Vleminckx V, Meijers B, Stork S, Ruehlicke T, Van Houtte E, Klaassen H, Celio MR, Missiaen L: Protective effect of parvalbumin on excitotoxic motor neuron death. Exp Neurol. 2002, 174: 150-161.

PubMedGoogle Scholar

Mattson MP, LaFerla FM, Chan SL, Leissring MA, Shepel PN, Geiger JD: Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2000, 23: 222-229.

PubMedGoogle Scholar

Radi R, Rubbo H, Bush K, Freeman BA: Xanthine oxidase binding to glycosaminoglycans: kinetics and superoxide dismutase interactions of immobilized xanthine oxidase-heparin complexes. Arch Biochem Biophys. 1997, 339: 125-135.

PubMedGoogle Scholar

Sasaki S, Iwata M: Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett. 1996, 204 (1–2): 53-56.

PubMedGoogle Scholar

Sasaki S, Warita H, Murakami T, Abe K, Iwata M: Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol. 2004, 107: 461-474.

PubMedGoogle Scholar

Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL: An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995, 14: 1105-1116.

PubMedGoogle Scholar

Kong J, Xu Z: Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998, 18: 3241-3250.

PubMedGoogle Scholar

Mattiazzi M, D’Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G: Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem. 2002, 277: 29626-29633.

PubMedGoogle Scholar

Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA: Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002, 80: 616-625.

PubMedGoogle Scholar

Fujita K, Yamauchi M, Shibayama K, Ando M, Honda M, Nagata Y: Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. J Neurosci Res. 1996, 45: 276-281.

PubMedGoogle Scholar

Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM: Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999, 46: 787-790.

PubMedGoogle Scholar

Jaiswal MK: Calcium, mitochondria and the pathogenesis of ALS: the good, the Bad and the ugly. Front Cell Neurosci. 2013, 7: 199-

PubMedCentralPubMedGoogle Scholar

Carriedo SG, Sensi SL, Yin HZ, Weiss JH: AMPA exposures induce mitochondrial Ca2+ overload and ROS generation in spinal motor neurons in vitro. J Neurosci. 2000, 20: 240-250.

PubMedGoogle Scholar

Beal MF: Oxidatively modified proteins in aging and disease. Free Radic Biol Med. 2002, 32: 797-803.

PubMedGoogle Scholar

Menzies FM, Cookson MR, Taylor RW, Turnbull DM, Chrzanowska-Lightowlers ZM, Dong L, Figlewicz DA, Shaw PJ: Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain. 2002, 125: 1522-1533.

PubMedGoogle Scholar

Beers DR, Ho BK, Siklos L, Alexianu ME, Mosier DR, Habib Mohamed A, Otsuka Y, Kozovska ME, Smith RE, McAlhany RG, Appel SH: Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J Neurochem. 2001, 79: 499-509.

PubMedGoogle Scholar

Heath PR, Shaw PJ: Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve. 2002, 26 (4): 438-458.

PubMedGoogle Scholar

Rao SD, Weiss JH: Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004, 27: 17-23.

PubMedGoogle Scholar

Maragakis NJ, Rothstein JD: Glutamate transporters in neurologic disease. Arch Neurol. 2001, 58 (3): 365-370.

PubMedGoogle Scholar

Trotti D, Rolfs A, Danbolt NC, Brown RH, Hediger MA: SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci. 1999, 2: 427-433.

PubMedGoogle Scholar

Tateno M, Sadakata H, Tanaka M, Itohara S, Shin RM, Miura M, Masuda M, Aosaki T, Urushitani M, Misawa H, Takahashi R: Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. Hum Mol Genet. 2004, 13: 2183-2196.

PubMedGoogle Scholar

Rao SD, Yin HZ, Weiss JH: Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons. J Neurosci. 2003, 23: 2627-2633.

PubMedGoogle Scholar

Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K: Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007, 10 (5): 608-614.

PubMedCentralPubMedGoogle Scholar

Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S: Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007, 10: 615-622.

PubMedCentralPubMedGoogle Scholar

Boillée S, Vande Velde C, Cleveland DW: ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006, 52 (1): 39-59.

PubMedGoogle Scholar

Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008, 11 (3): 251-253.

PubMedCentralPubMedGoogle Scholar

Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW: Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006, 312 (5778): 1389-1392.

PubMedGoogle Scholar

Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, Cleveland DW: Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci U S A. 2009, 106 (11): 4465-4470.

PubMedCentralPubMedGoogle Scholar

Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC: Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci. 2008, 28 (9): 2075-2088.

PubMedGoogle Scholar

Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J, Burghes AH, Shaw PJ, Cleveland DW, Kolb SJ, Kaspar BK: Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A. 2014, 111: 829-832.

PubMedCentralPubMedGoogle Scholar

Foskett JK, White C, Cheung KH, Mak DO: Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev. 2007, 87 (2): 593-658.

PubMedCentralPubMedGoogle Scholar

Lu YM, Yin HZ, Weiss JH: Ca2+ permeable AMPA/kainate channels permit rapid injurious Ca2+ entry. Neuroreport. 1995, 6 (8): 1089-1092.

PubMedGoogle Scholar

Van Den Bosch L, Vandenberghe W, Klaassen H, Van Houtte E, Robberecht W: Ca2+-permeable AMPA receptors and selective vulnerability of motor neurons. J Neurol Sci. 2000, 180 (1–2): 29-34.

PubMedGoogle Scholar

Van Den Bosch L, Van Damme P, Vleminckx V, Van Houtte E, Lemmens G, Missiaen L, Callewaert G, Robberecht W: An alpha-mercaptoacrylic acid derivative (PD150606) inhibits selective motor neuron death via inhibition of kainate-induced Ca2+ influx and not via calpain inhibition. Neuropharmacology. 2002, 42 (5): 706-713.

PubMedGoogle Scholar

Van Damme P, Van Den Bosch L, Van Houtte E, Callewaert G, Robberecht W: GluR2-dependent properties of AMPA receptors determine the selective vulnerability of motor neurons to excitotoxicity. J Neurophysiol. 2002, 88 (3): 1279-1287.

PubMedGoogle Scholar

Palecek J, Lips MB, Keller BU: Calcium dynamics and buffering in motoneurones of the mouse spinal cord. J Physiol. 1999, 520 (Pt 2): 485-502.

PubMedCentralPubMedGoogle Scholar

DePaul R, Abbs JH, Caligiuri M, Gracco VL, Brooks BR: Hypoglossal, trigeminal, and facial motoneuron involvement in amyotrophic lateral sclerosis. Neurology. 1988, 38 (2): 281-

PubMedGoogle Scholar

von Lewinski F, Keller BU: Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS. Trends Neurosci. 2005, 28 (9): 494-500.

PubMedGoogle Scholar

Neher E: The use of fura-2 for estimating Ca2+ buffers and Ca2+ fluxes. Neuropharmacology. 1995, 34: 1423-1442.

PubMedGoogle Scholar

Palecek J, Keller BU: Differential calcium buffering in motoneuron populations that are selectively vulnerable and resistant in motoneuron disease. Pflugers Arch. 2000, Supplement, Vol. 439, pR333

Google Scholar

Ladewig T, Keller BU: Simultaneous patch-clamp recording and calcium imaging in a rhythmically active neuronal network in the brainstem slice preparation from mouse. Pflugers Arch. 2000, 440: 322-332.

PubMedGoogle Scholar

Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW: Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995, 38 (1): 73-84.

PubMedGoogle Scholar

Carriedo SG, Yin HZ, Sensi SL, Weiss JH: Rapid Ca2+ entry through Ca2+ - permeable AMPA/Kainate channels triggers marked intracellular Ca2+ rises and consequent oxygen radical production. J Neurosci. 1998, 18: 7727-7738.

PubMedGoogle Scholar

Shaw PJ, Ince PG: Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J Neurol. 1997, 244 (Suppl. 2): S3-S14.

PubMedGoogle Scholar

Cleveland DW: From charcot to SOD1: Mechanisms of selective motor neuron death in ALS. Neuron. 1999, 24: 515-520.

PubMedGoogle Scholar

Nägerl UV, Mody I: Calcium-dependent inactivation of high-threshold calcium currents in human dentate gyrus granule cells. J Physiol. 1998, 509: 39-45.

PubMedCentralPubMedGoogle Scholar

Kruman II, Pedersen WA, Springer JE, Mattson MP: ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp Neurol. 1999, 160 (1): 28-39.

PubMedGoogle Scholar

Simpson EP, Yen AA, Appel SH: Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Curr Opin Rheumatol. 2003, 15 (6): 730-736.

PubMedGoogle Scholar

Goodall EF, Morrison KE: Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Expert Rev Mol Med. 2006, 8 (11): 1-22.

PubMedGoogle Scholar

Strong MJ: The basic aspects of therapeutics in amyotrophic lateral sclerosis. Pharmacol Ther. 2003, 98: 379-414.

PubMedGoogle Scholar

Liu D, Wen J, Liu J, Li L: The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J. 1999, 13: 2318-

PubMedGoogle Scholar

Sau D, Rusmini P, Crippa V, Onesto E, Bolzoni E, Ratti A, Poletti A: Dysregulation of axonal transport and motorneuron diseases. Biol Cell. 2011, 103: 87-107.

PubMedGoogle Scholar

Gunawardena S, Goldstein LS: Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol. 2004, 58: 258-271.

PubMedGoogle Scholar

Perlson E, Jeong GB, Ross JL, Dixit R, Wallace KE, Kalb RG, Holzbaur EL: A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci. 2009, 29: 9903-9917.

PubMedCentralPubMedGoogle Scholar

Beal MF: Mitochondria and the pathogenesis of ALS. Brain. 2000, 123: 1291-1292.

PubMedGoogle Scholar

Kawamata H, Manfredi G: Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech Ageing Dev. 2010, 131: 517-526.

PubMedCentralPubMedGoogle Scholar

Magrané J, Cortez C, Gan WB, Manfredi G: Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet. 2013, Nov. 25 [Epub ahead of print]

Google Scholar

Magrané J, Sahawneh MA, Przedborski S, Estévez ÁG, Manfredi G: Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci. 2012, 32: 229-242.

PubMedCentralPubMedGoogle Scholar

Cozzolino M, Ferri A, Valle C, Carri MT: Mitochondria and ALS: implications from novel genes and pathways. Mol Cell Neurosci. 2013, 55: 44-49.

PubMedGoogle Scholar

Cozzolino M, Carrì MT: Mitochondrial dysfunction in ALS. Prog Neurobiol. 2012, 97 (2): 54-66.

PubMedGoogle Scholar

Vijayvergiya C, Beal MF, Buck J, Manfredi G: Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J Neurosci. 2005, 25 (10): 2463-2470.

PubMedGoogle Scholar

Vande Velde C, Miller TM, Cashman NR, Cleveland DW: Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A. 2008, 105 (10): 4022-4027.

PubMedCentralPubMedGoogle Scholar

Vande Velde C, McDonald KK, Boukhedimi Y, McAlonis-Downes M, Lobsiger CS, Bel Hadj S, Zandona A, Julien JP, Shah SB, Cleveland DW: Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One. 2011, 6 (7): e22031-doi:10.1371/journal.pone.0022031

PubMedCentralPubMedGoogle Scholar

Bowling AC, Schulz JB, Brown RH, Beal MF: Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1993, 61 (6): 2322-2325.

PubMedGoogle Scholar

Browne SE, Bowling AC, Baik MJ, Gurney M, Brown RH, Beal MF: Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem. 1998, 71: 281-287.

PubMedGoogle Scholar

Jaarsma D, Rognoni F, Duijn WV, Verspaget HW, Haasdijk ED, Holstege JC: Cu- Zn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropath. 2001, 102: 293-305.

PubMedGoogle Scholar

Hirano A, Nakano I, Kurland LT, Mulder DW, Holley PW, Saccomanno G: Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1984, 43: 471-480.

PubMedGoogle Scholar

Hirano A: Cytopathology of amyotrophic lateral sclerosis. Adv Neurol. 1991, 56: 91-101.

PubMedGoogle Scholar

Siklos L, Engelhardt J, Harati Y, Smith RG, Joo F, Appel SH: Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol. 1996, 39: 203-216.

PubMedGoogle Scholar

Jaiswal MK, Zech W, Goos M, Leutbecher C, Ferri A, Zippelius A, Carrì MT, Nau R, Keller BU: Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease. BMC Neurosci. 2009, 10: 64-

PubMedCentralPubMedGoogle Scholar

Wiedemann FR, Winkler K, Kuznetsov AV, Bartels C, Vielhaber S, Feistner H, Kunz WS: Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci. 1998, 156 (1): 65-72.

PubMedGoogle Scholar

Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, Feistner H, Heinze HJ, Elger CE, Schubert W, Kunz WS: Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain. 2000, 123 (Pt 7): 1339-1348.

PubMedGoogle Scholar

Swerdlow RH, Parks JK, Cassarino DS, Trimmer PA, Miller SW, Maguire DJ, Sheehan JP, Maguire RS, Pattee G, Juel VC: Mitochondria in sporadic amyotrophic lateral sclerosis. Exp Neurol. 1998, 153: 135-142.

PubMedGoogle Scholar

Kruman II, Mattson MP: Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J Neurochem. 1999, 72 (2): 529-540.

PubMedGoogle Scholar

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

PubMedCentralPubMedGoogle Scholar

Kirkinezos IG, Bacman SR, Hernandez D, Oca-Cossio J, Arias LJ, Perez-Pinzon MA, Bradley WG, Moraes CT: Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. J Neurosci. 2005, 5 (25): 164-172.

Google Scholar

Dal Canto MC, Gurney ME: Neuropathological changes in two lines of mice carrying 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. 1995, 676: 25-40.

PubMedGoogle Scholar

Bendotti C, Calvaresi N, Chiveri L, Prelle A, Moggio M, Braga M, Silani V, De Biasi S: Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J Neurol Sci. 2001, 191: 25-33.

PubMedGoogle Scholar

Higgins CMJ, Jung C, Xu Z: ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 2003, 4: 16-

PubMedCentralPubMedGoogle Scholar

Xu Z, Jung C, Higgins C, Levine J, Kong J: Mitochondrial degeneration in amyotrophic lateral sclerosis. J Bioenerg Biomembr. 2004, 36: 395-399.

PubMedGoogle Scholar

Liu J, Lillo C, Jonsson PA, Vande Velde C, Ward CM, Miller TM, Subramaniam JR, Rothstein JD, Marklund S, Andersen PM, Brännström T, Gredal O, Wong PC, Williams DS, Cleveland DW: Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004, 43: 5-17.

PubMedGoogle Scholar

Parone PA, Da Cruz S, Han JS, McAlonis-Downes M, Vetto AP, Lee SK, Tseng E, Cleveland DW: Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J Neurosci. 2013, 33: 4657-4671.

PubMedCentralPubMedGoogle Scholar

Kaal EC, Vlug AS, Versleijen MW, Kuilman M, Joosten EA, Bar PR: Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis. J Neurochem. 2000, 74: 1158-1165.

PubMedGoogle Scholar

Tovar-y-Romo LB: Tapia, R: Delayed administration of VEGF rescues spinal motor neurons from death with a short effective time frame in excitotoxic experimental models in vivo. ASN Neuro. 2012, 4: e00081-

PubMedCentralPubMedGoogle Scholar

Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL: Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. Dev Neurobiol. 2009, 69: 871-884.

PubMedCentralPubMedGoogle Scholar

Bogaert E, Van Damme P, Poesen K, Dhondt J, Hersmus N, Kiraly D, Scheveneels W, Robberecht W, Van Den Bosch L: VEGF protects motor neurons against excitotoxicity by upregulation of GluR2. Neurobiol Aging. 2010, 31: 2185-2191.

PubMedGoogle Scholar

Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001, 28: 131-138.

PubMedGoogle Scholar

Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003, 34: 383-394.

PubMedGoogle Scholar

Zheng C, Nennesmo I, Fadeel B, Henter JI: Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS. Ann Neurol. 2004, 56: 564-567.

PubMedGoogle Scholar

Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND: VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature. 2004, 429: 413-417.

PubMedGoogle Scholar

Wang Y, Ou Mao X, Xie L, Banwait S, Marti HH, Greenberg DA, Jin K: Vascular endothelial growth factor overexpression delays neurodegeneration and prolongs survival in amyotrophic lateral sclerosis mice. J Neurosci. 2007, 27: 304-307.

PubMedCentralPubMedGoogle Scholar

Lambrechts D, Poesen K, Fernández-Santiago R, Al-Chalabi A, Del Bo R, Van Vught PW, Khan S, Marklund SL, Brockington A, van Marion I, Anneser J, Shaw C, Ludolph AC, Leigh NP, Comi GP, Gasser T, Shaw PJ, Morrison KE, Andersen PM, Van den Berg LH, Thijs V, Siddique T, Robberecht W, Carmeliet P: Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. J Med Genet. 2009, 46: 840-846.

PubMedGoogle Scholar

Dodge JC, Haidet AM, Yang W, Passini MA, Hester M, Clarke J, Roskelley EM, Treleaven CM, Rizo L, Martin H, Kim SH, Kaspar R, Taksir TV, Griffiths DA, Cheng SH, Shihabuddin LS, Kaspar BK: Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol Ther. 2008, 16: 1056-1064.

PubMedCentralPubMedGoogle Scholar

Vanselow BK, Keller BU: Calcium dynamics and buffering in oculomotor neurones from mouse those are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motoneuron disease. J Physiol. 2000, 525: 433-445.

PubMedCentralPubMedGoogle Scholar

Elliott JL, Snider WD: Parvalbumin is a marker of ALS-resistant motor neurons. Neuroreport. 1995, 6 (3): 449-452.

PubMedGoogle Scholar

Zhou Z, Neher E: Mobile and immobile calcium buffers in bovine adrenal chromaffin cells. J Physiol. 1993, 469: 245-273.

PubMedCentralPubMedGoogle Scholar

Klingauf J, Neher E: Modeling buffered Ca2+ diffusion near the membrane: implications for secretion in neuroendocrine cells. Biophys J. 1997, 72: 674-690.

PubMedCentralPubMedGoogle Scholar

Lips MB, Keller BU: Activity-related calcium dynamics in motoneurons of the nucleus hypoglossus from mouse. J Neurophysiol. 1999, 82: 2936-2946.

PubMedGoogle Scholar

Dekkers J, Bayley P, Dick JR, Schwaller B, Berchtold MW, Greensmith L: Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death. Neuroscience. 2004, 123 (2): 459-466.

PubMedGoogle Scholar

Rizzuto R, Brini M, Pozzan T: Intracellular targeting of the photoprotein aequorin: a new approach for measuring, in living cells, Ca2+ concentrations in defined cellular compartments. Cytotechnology. 1993, 11: 44-46.

Google Scholar

Roy J, Minotti S, Dong L, Figlewicz DA, Durham HD: Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci. 1998, 18: 9673-9684.

PubMedGoogle Scholar

Maragakis NJ, Rothstein JD: Glutamate transporters: animal models to neurologic disease. Neurobiol Dis. 2004, 15 (3): 461-473.

PubMedGoogle Scholar

Morotz GM, De Vos KJ, Vagnoni A, Ackerley S, Shaw CE, Miller CC: Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet. 2012, 21: 1979-1988.

PubMedCentralPubMedGoogle Scholar

De Vos KJ, Mórotz GM, Stoica R, Tudor EL, Lau KF, Ackerley S, Warley A, Shaw CE, Miller CC: VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet. 2012, 21: 1299-1311.

PubMedCentralPubMedGoogle Scholar

Appel SH, Smith RG, Alexianu M, Siklos L, Engelhardt J, Colom LV, Stefani E: Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis. Clin Neurosci. 1995, 6: 368-374.

Google Scholar

Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ: Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci. 1998, 1 (5): 366-373.

PubMedGoogle Scholar

Choi D, Koh J, Peters S: Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci. 1988, 8: 185-196.

PubMedGoogle Scholar

Shaw PJ, Forest V, Ince PG, Richardson JP, Wastell HJ: CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration. 1995, 4 (2): 209-216.

PubMedGoogle Scholar

Carriedo SG, Yin HZ, Weiss JH: Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci. 1996, 16: 4069-4079.

PubMedGoogle Scholar

Jia Z, Agopyan N, Miu P, Xiong Z, Henderson J, Gerlai R, Taverna FA, Velumian A, MacDonald J, Carlen P, Abramow-Newerly W, Roder J: Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron. 1996, 17: 945-956.

PubMedGoogle Scholar

Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996, 16: 675-686.

PubMedGoogle Scholar

Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, Andrus PK, Hall ED: Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996, 39 (2): 147-157.

PubMedGoogle Scholar

Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH: Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 2000, 406: 78-81.

PubMedGoogle Scholar

Kuner R, Groom AJ, Bresink I, Kornau HC, Stefovska V, Müller G, Hartmann B, Tschauner K, Waibel S, Ludolph AC, Ikonomidou C, Seeburg PH, Turski L: Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit. Proc Natl Acad Sci U S A. 2005, 102: 5826-5831.

PubMedCentralPubMedGoogle Scholar

Schinder AF, Olson EC, Spitzer NC, Montal M: Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci. 1996, 16: 6125-6133.

PubMedGoogle Scholar

Arnaudeau S, Kelley WL, Walsh JV, Demaurex N: Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J Biol Chem. 2001, 276: 29430-29439.

PubMedGoogle Scholar

Szabadkai G, Simoni AM, Rizzuto R: Mitochondrial Ca2+ uptake requires sustained Ca2+ release from the endoplasmic reticulum. J Biol Chem. 2003, 278: 15153-15161.

PubMedGoogle Scholar

Rothstein JD, Martin LJ, Kuncl RW: Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med. 1992, 326 (22): 1464-1468.

PubMedGoogle Scholar

Baron KT, Wang GJ, Padua RA, Campbell C, Thayer SA: NMDA-evoked consumption and recovery of mitochondrially targeted aequorin suggests increased Ca2+ uptake by a subset of mitochondria in hippocampal neurons. Brain Res. 2003, 993: 124-132.

PubMedGoogle Scholar

Malli R, Frieden M, Osibow K, Zoratti C, Mayer M, Demaurex N, Graier WF: Sustained Ca2+ transfer across mitochondria is essential for mitochondrial Ca2+ buffering, store-operated Ca2+entry, and Ca2+ store refilling. J Biol Chem. 2003, 45: 44769-44779.

Google Scholar

Rizzuto R, Bernardi P, Pozzan T: Mitochondria as all-round players of the calcium game. J Physiol. 2000, 529: 37-47.

PubMedCentralPubMedGoogle Scholar

Corona JC, Tapia R: Ca2+-permeable AMPA receptors and intracellular Ca2+ determine motoneuron vulnerability in rat spinal cord in vivo. Neuropharmacology. 2007, 52: 1219-1228.

PubMedGoogle Scholar

Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD: Calcium and mitochondria. FEBS Lett. 2004, 567: 6-102.

Google Scholar

Rizzuto R, Bastianutto C, Brini M, Murgia M, Pozzan T: Mitochondrial Ca2+ homeostasis in intact cells. J Cell Biol. 1994, 126: 1183-1194.

PubMedGoogle Scholar

Rizzuto R: Calcium mobilization from mitochondria in synaptic transmitter release. J Cell Biol. 2003, 163: 441-443.

PubMedCentralPubMedGoogle Scholar

Rutter GA, Burnett P, Rizzuto R, Brini M, Murgia M, Pozzan T, Tavaré JM, Denton RM: Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: Significance for the regulation of pyruvate dehydrogenase activity. Proc Natl Acad Sci U S A. 1996, 93: 5489-5494.

PubMedCentralPubMedGoogle Scholar

Ladewig T, Kloppenburg P, Lalley PM, Zipfel WR, Webb WW, Keller BU: Spatial profiles of store-dependent calcium release in motoneurones of the nucleus hypoglossus from newborn mouse. J Physiol. 2003, 547: 775-787.

PubMedCentralPubMedGoogle Scholar

Duchen MR: Mitochondria and Ca2+ in cell physiology and pathophysiology. Cell Calcium. 2000, 28: 339-348.

PubMedGoogle Scholar

Rizzuto R, Duchen MR, Pozzan T: Flirting in little space: the ER/mitochondria Ca2+ liaison. Sci STKE. 2004, 13 (215): re1-

Google Scholar

Goos M, Zech WD, Jaiswal MK, Balakrishnan S, Ebert S, Mitchell T, Carrì MT, Keller BU, Nau R: Expression of a Cu,Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of neuroblastoma cells to infectious injury. BMC Infect Dis. 2007, 12 (7): 131-

Google Scholar

Pivovarova NB, Nguyen HV, Winters CA, Brantner CA, Smith CL, Andrews SB: Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons. J Neurosci. 2004, 24: 5611-5622.

PubMedGoogle Scholar

Shaw PJ: Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005, 76: 1046-1057.

PubMedCentralPubMedGoogle Scholar

Genç B, Ozdinler PH: Moving forward in clinical trials for ALS: motor neurons lead the way please. Drug Discov Today. 2013, doi:10.1016/j.drudis.2013.10.014. [Epub ahead of print]

Google Scholar

Carri MT, Grignaschi G, Bendotti C: Targets in ALS: designing multidrug therapies. Trends Pharmacol Sci. 2006, 27 (5): 267-273.

PubMedGoogle Scholar

Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH: Retrograde viral delivery of IGF-1 prolongs sur vival in a mouse ALS model. Science. 2003, 301: 839-842.

PubMedGoogle Scholar

Tolosa L, Mir M, Asensio VJ, Olmos G, Llado J: Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem. 2008, 105: 1080-1090.

PubMedGoogle Scholar

Tovar-y-Romo LB, Tapia R: VEGF protects spinal motor neurons against chronic excitotoxic degeneration in vivo by activation of PI3-K pathway and inhibition of p38MAPK. J Neurochem. 2010, 115: 1090-1101.

PubMedGoogle Scholar

Zhang W, Narayanan M, Friedlander RM: Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003, 53: 267-270.

PubMedGoogle Scholar

Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD, Sanberg PR: Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematotherapy Stem Cell Res. 2003, 12: 255-270.

Google Scholar

Lepore AC, Maragakis NJ: Targeted stem cell transplantation strategies in ALS. Neurochem Internat. 2007, 50: 966-975.

Google Scholar

Bova MP, Kinney GG: Emerging drug targets in amyotrophic lateral sclerosis. Expert Opin Orphan Drugs. 2013, 1 (1): 5-20.

Google Scholar

Published
2019-01-30
Section
Review