Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies

References

• Mulder DW, Kurland LT, Offord KP, Beard CM. Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology 36(4) 511–517 (1986).
   PubMed Web of Science ®Google Scholar
• Cudkowicz ME, McKenna-Yasek D, Sapp PE et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41(2) 210–221 (1997).
   PubMed Web of Science ®Google Scholar
• Leigh PN, Swash M. Cytoskeletal pathology in motor neuron diseases. Adv. Neurol. 56, 115–124 (1991).
   PubMedGoogle Scholar
• Delisle MB, Carpenter S. Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J. Neurol. Sci. 63(2), 241–250 (1984).
   PubMed Web of Science ®Google Scholar
• Miller RG, Rosenberg JA, Gelinas DF et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review), report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 52(7), 1311–1323 (1999).
   PubMed Web of Science ®Google Scholar
• Van den Berg JP, Kalmijn S, Lindeman E et al. Multidisciplinary ALS care improves quality of life in patients with ALS. Neurology 65(8), 1264–1267 (2005).
   PubMed Web of Science ®Google Scholar
• Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J. Neurol. Neurosurg. Psychiatry 74(9), 1258–1261 (2003).
   PubMed Web of Science ®Google Scholar
• Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 330(9), 585–591 (1994).
   PubMed Web of Science ®Google Scholar
• Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347(9013), 1425–1431 (1996).
   PubMed Web of Science ®Google Scholar
• Gurney ME, Fleck TJ, Himes CS, Hall ED. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 50(1), 62–66 (1998).
   PubMed Web of Science ®Google Scholar
• Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004).
   PubMed Web of Science ®Google Scholar
• Rosen DR, Siddique T, Patterson D et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415), 59–62 (1993).
   PubMed Web of Science ®Google Scholar
• Nishimura AL, Mitne-Neto M, Silva HC et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75(5), 822–831 (2004).
   PubMed Web of Science ®Google Scholar
• Abalkhail H, Mitchell J, Habgood J, Orrell R, de Belleroche J. A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1–16q12.2. Am. J. Hum. Genet. 73(2), 383–389 (2003).
   PubMed Web of Science ®Google Scholar
• Sapp PC, Hosler BA, McKenna-Yasek D et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am. J. Hum. Genet. 73(2), 397–403 (2003).
   PubMed Web of Science ®Google Scholar
• Ruddy DM, Parton MJ, Al-Chalabi A et al. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am. J. Hum. Genet. 73(2), 390–396 (2003).
   PubMed Web of Science ®Google Scholar
• Hadano S, Hand CK, Osuga H et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genet. 29(2), 166–173 (2001).
   PubMed Web of Science ®Google Scholar
• Chen YZ, Bennett CL, Huynh HM et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74(6), 1128–1135 (2004).
   PubMed Web of Science ®Google Scholar
• Puls I, Jonnakuty C, LaMonte BH et al. Mutant dynactin in motor neuron disease. Nature Genet. 33(4), 455–456 (2003).
   PubMed Web of Science ®Google Scholar
• Andersen PM. Genetic factors in the early diagnosis of ALS. Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 1(Suppl. 1), S31–S42 (2000).
   Google Scholar
• Andersen PM, Spitsyn VA, Makarov SV et al. The geographical and ethnic distribution of the D90A CuZn–SOD mutation in the Russian Federation. Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 2(2), 63–69 (2001).
   PubMed Web of Science ®Google Scholar
• Gaudette M, Hirano M, Siddique T. Current status of SOD1 mutations in familial amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 1(2), 83–89 (2000).
   PubMed Web of Science ®Google Scholar
• Reaume AG, Elliott JL, Hoffman EK et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nature Genet. 13(1), 43–47 (1996).
   PubMed Web of Science ®Google Scholar
• Bruijn LI, Houseweart MK, Kato S et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281(5384), 1851–1854 (1998).
   PubMed Web of Science ®Google Scholar
• Borchelt DR, Lee MK, Slunt HS et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc. Natl Acad. Sci. USA 91(17), 8292–8296 (1994).
   PubMed Web of Science ®Google Scholar
• Bowling AC, Barkowski EE, McKenna-Yasek D et al. Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis. J. Neurochem. 64(5), 2366–2369 (1995).
   PubMed Web of Science ®Google Scholar
• Bruijn LI, Cleveland DW. Mechanisms of selective motor neuron death in ALS: insights from transgenic mouse models of motor neuron disease. Neuropathol. Appl. Neurobiol. 22(5), 373–387 (1996).
   PubMed Web of Science ®Google Scholar
• Gurney ME. Transgenic-mouse model of amyotrophic lateral sclerosis. N. Engl. J. Med. 331(25), 1721–1712 (1994).
   PubMed Web of Science ®Google Scholar
• Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 92(3), 689–693 (1995).
   PubMed Web of Science ®Google Scholar
• Gurney ME, Pu H, Chiu AY et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264(5166), 1772–1775 (1994).
   PubMed Web of Science ®Google Scholar
• Wong PC, Pardo CA, Borchelt DR et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14(6), 1105–1116 (1995).
   PubMed Web of Science ®Google Scholar
• Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20(2), 660–665 (2000).
   PubMed Web of Science ®Google Scholar
• Lino MM, Schneider C, Caroni P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22(12), 4825–4832 (2002).
   PubMed Web of Science ®Google Scholar
• Clement AM, Nguyen MD, Roberts EA et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642), 113–117 (2003).
   PubMed Web of Science ®Google Scholar
• Rothstein JD. Excitotoxicity hypothesis. Neurology 47(Suppl. 2), S19–S26 (1996).
   PubMedGoogle Scholar
• Tanaka K, Watase K, Manabe T et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276(5319), 1699–1702 (1997).
   PubMed Web of Science ®Google Scholar
• Rothstein JD, Tsai G, Kuncl RW et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann. Neurol. 28(1), 18–25 (1990).
   PubMed Web of Science ®Google Scholar
• Rothstein JD, Kuncl R, Chaudhry V et al. Excitatory amino acids in amyotrophic lateral sclerosis: an update. Ann. Neurol. 30(2), 224–225 (1991).
   PubMed Web of Science ®Google 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. 38(1), 73–84 (1995).
   PubMed Web of Science ®Google Scholar
• Trotti D, Aoki M, Pasinelli P et al. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity. J. Biol. Chem. 276(1), 576–582 (2001).
   PubMed Web of Science ®Google Scholar
• Kawahara Y, Kwak S. Excitotoxicity and ALS: what is unique about the AMPA receptors expressed on spinal motor neurons? Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 6(3), 131–144 (2005).
   PubMed Web of Science ®Google Scholar
• Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S. Glutamate receptors: RNA editing and death of motor neurons. Nature 427(6977), 801 (2004).
   PubMed Web of Science ®Google Scholar
• Kwak S, Kawahara Y. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J. Mol. Med. 83(2), 110–120 (2005).
   PubMed Web of Science ®Google Scholar
• Van Damme P, Braeken D, Callewaert G, Robberecht W, Van Den Bosch L. GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 64(7), 605–612 (2005).
   PubMed Web of Science ®Google Scholar
• Selkoe DJ. Presenilin, Notch, and the genesis and treatment of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 98(20), 11039–11041 (2001).
   PubMed Web of Science ®Google Scholar
• Steffan JS, Bodai L, Pallos J et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413(6857), 739–743 (2001).
   PubMed Web of Science ®Google Scholar
• Wang J, Xu G, Borchelt David R. High molecular weight complexes of mutant superoxide dismutase 1: age-dependent and tissue-specific accumulation. Neurobiol. Dis. 139–148 (2002).
   PubMed Web of Science ®Google Scholar
• Kato S, Takikawa M, Nakashima K et al. New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes. Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 1(3), 163–184 (2000).
   PubMed Web of Science ®Google Scholar
• Mather K, Martin JE, Swash M, Vowles G, Brown A, Leigh PN. Histochemical and immunocytochemical study of ubiquitinated neuronal inclusions in amyotrophic lateral sclerosis. Neuropathol. Appl. Neurobiol. 19(2), 141–145 (1993).
   PubMed Web of Science ®Google Scholar
• Leigh PN, Whitwell H, Garofalo O et al. Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114(Pt 2), 775–788 (1991).
   PubMed Web of Science ®Google Scholar
• Wang J, Xu G, Slunt HH et al. Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. 20(3), 943–952 (2005).
   Google Scholar
• Matsumoto G, Stojanovic A, Holmberg CI, Kim S, Morimoto RI. Structural properties and neuronal toxicity of amyotrophic lateral sclerosis-associated Cu/Zn superoxide dismutase 1 aggregates. J. Cell Biol. 171(1), 75–85 (2005).
   PubMed Web of Science ®Google Scholar
• Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A. Monomeric Cu,Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic lateral sclerosis. J. Biol. Chem. 279(15), 15499–15504 (2004).
   PubMed Web of Science ®Google Scholar
• Ray SS, Lansbury PT Jr. A possible therapeutic target for Lou Gehrig’s disease. Proc. Natl Acad. Sci. USA 101(16), 5701–5702 (2004).
   PubMed Web of Science ®Google Scholar
• Corcoran LJ, Mitchison TJ, Liu Q. A novel action of histone deacetylase inhibitors in a protein aggresome disease model. Curr. Biol. 14(6), 488–492 (2004).
   PubMed Web of Science ®Google Scholar
• Shinder GA, Lacourse MC, Minotti S, Durham HD. Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis. J. Biol. Chem. 276(16), 12791–12796 (2001).
   PubMed Web of Science ®Google Scholar
• Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nature Med. 10(4), 402–405 (2004).
   PubMed Web of Science ®Google Scholar
• Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am. J. Pathol. 145(6), 1271–1279 (1994).
   PubMed Web of Science ®Google 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. 18(9), 3241–3250 (1998).
   PubMed Web of Science ®Google Scholar
• Mattiazzi M, D'Aurelio M, Gajewski CD et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277(33), 29626–29633 (2002).
   PubMed Web of Science ®Google Scholar
• Higgins CM, Jung C, Ding H, Xu Z. Mutant Cu, Zn Superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J. Neurosci. 22(6), RC215 (2002).
   PubMed Web of Science ®Google Scholar
• Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta. Neuropathol. (Berl.) 102(4), 293–305 (2001).
   PubMed Web of Science ®Google Scholar
• Liu J, Lillo C, Jonsson PA et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43(1), 5–17 (2004).
   PubMed Web of Science ®Google Scholar
• Pasinelli P, Belford ME, Lennon N et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43(1), 19–30 (2004).
   PubMed Web of Science ®Google Scholar
• Klivenyi P, Ferrante RJ, Matthews RT et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nature Med. 5(3), 347–350 (1999).
   PubMed Web of Science ®Google Scholar
• Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 13(8), 1067–1070 (2002).
   PubMed Web of Science ®Google Scholar
• Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 10(3), 268–278 (2002).
   PubMed Web of Science ®Google Scholar
• Groeneveld GJ, Veldink JH, van der Tweel I et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann. Neurol. 53(4), 437–445 (2003).
   PubMed Web of Science ®Google Scholar
• Shefner JM, Cudkowicz ME, Schoenfeld D et al. A clinical trial of creatine in ALS. Neurology 63(9), 1656–1661 (2004).
   PubMed Web of Science ®Google Scholar
• Lee MK, Cleveland DW. Neuronal intermediate filaments. Annu. Rev. Neurosci. 19, 187–217 (1996).
   PubMed Web of Science ®Google Scholar
• Kawamura Y, Dyck PJ, Shimono M, Okazaki H, Tateishi J, Doi H. Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 40(6), 667–675 (1981).
   PubMed Web of Science ®Google Scholar
• Bruijn LI, Becher MW, Lee MK et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18(2), 327–338 (1997).
   PubMed Web of Science ®Google Scholar
• Vechio JD, Bruijn LI, Xu Z, Brown RH Jr. Cleveland DW. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann. Neurol. 40(4), 603–610 (1996).
   PubMed Web of Science ®Google Scholar
• Garcia ML, Singleton AB, Hernandez D et al. Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis. Neurobiol. Dis. (2005).
   PubMed Web of Science ®Google Scholar
• Al-Chalabi A, Andersen PM, Nilsson P et al. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum. Mol. Genet. 8(2), 157–164 (1999).
   PubMed Web of Science ®Google Scholar
• Figlewicz DA, Krizus A, Martinoli MG et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum. Mol. Genet. 3(10), 1757–1761 (1994).
   PubMed Web of Science ®Google Scholar
• Tomkins J, Usher P, Slade JY et al. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport 9(17), 3967–3970 (1998).
   PubMed Web of Science ®Google Scholar
• LaMonte BH, Wallace KE, Holloway BA et al. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34(5), 715–727 (2002).
   PubMed Web of Science ®Google Scholar
• Hafezparast M, Klocke R, Ruhrberg C et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300(5620), 808–812 (2003).
   PubMed Web of Science ®Google Scholar
• Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 97(25), 13901–13906 (2000).
   PubMed Web of Science ®Google Scholar
• Vukosavic S, Stefanis L, Jackson-Lewis V et al. Delaying caspase activation by Bcl-2: a clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 20(24), 9119–9125 (2000).
   PubMed Web of Science ®Google Scholar
• Li M, Ona VO, Guegan C et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288(5464), 335–339 (2000).
   PubMed Web of Science ®Google Scholar
• Kostic V, Gurney ME, Deng HX, Siddique T, Epstein CJ, Przedborski S. Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ann. Neurol. 41(4), 497–504 (1997).
   PubMed Web of Science ®Google Scholar
• Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57(7), 1282–1289 (2001).
   PubMed Web of Science ®Google Scholar
• Elliott JL. Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res. Mol. Brain Res. 95(1–2), 172–178 (2001).
   PubMedGoogle Scholar
• Nguyen MD, Julien JP, Rivest S. Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1β in neurodegeneration. Ann. Neurol. 50(5), 630–639 (2001).
   PubMed Web of Science ®Google Scholar
• Hensley K, Floyd RA, Gordon B et al. Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A–SOD1 mouse model of amyotrophic lateral sclerosis. J. Neurochem. 82(2), 365–374 (2002).
   PubMed Web of Science ®Google Scholar
• Drachman DB, Rothstein JD. Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis. Ann. Neurol. 48(5), 792–795 (2000).
   PubMed Web of Science ®Google Scholar
• Rothstein JD, Patel S, Regan MR et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021), 73–77 (2005).
   PubMed Web of Science ®Google Scholar
• Crow JP, Calingasan NY, Chen J, Hill JL, Beal MF. Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann. Neurol. 58(2), 258–265 (2005).
   PubMed Web of Science ®Google Scholar
• Heemskerk J, Tobin AJ, Bain LJ. Teaching old drugs new tricks. Meeting of the Neurodegeneration Drug Screening Consortium, 7–8 April, Washington, DC, USA. Trends Neurosci. 25(10), 494–496 (2002).
   PubMed Web of Science ®Google Scholar
• Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc. Natl Acad. Sci. USA 95(15), 8892–8897 (1998).
   PubMed Web of Science ®Google Scholar
• Zhu S, Stavrovskaya IG, Drozda M et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417(6884), 74–78 (2002).
   PubMed Web of Science ®Google Scholar
• Ryu H, Smith K, Camelo SI et al. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J. Neurochem. 93(5), 1087–1098 (2005).
   Google Scholar
• Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301(5634), 839–842 (2003).
   PubMed Web of Science ®Google Scholar
• Oosthuyse B, Moons L, Storkebaum E et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28(2), 131–138 (2001).
   PubMed Web of Science ®Google Scholar
• Lambrechts D, Storkebaum E, Morimoto M et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34(4), 383–394 (2003).
   PubMed Web of Science ®Google Scholar
• Azzouz M, Ralph GS, Storkebaum E et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429(6990), 413–417 (2004).
   PubMed Web of Science ®Google Scholar
• Storkebaum E, Lambrechts D, Dewerchin M et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8(1), 85–92 (2005).
   PubMed Web of Science ®Google Scholar
• Ding H, Schwarz DS, Keene A et al. Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell 2(4), 209–217 (2003).
   PubMed Web of Science ®Google Scholar
• Raoul C, Abbas-Terki T, Bensadoun JC et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nature Med. 11(4), 423–428 (2005).
   PubMed Web of Science ®Google Scholar
• Ralph GS, Radcliffe PA, Day DM et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nature Med. 11(4), 429–433 (2005).
   PubMed Web of Science ®Google Scholar
• Miller TM, Kaspar BK, Kops GJ et al. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann. Neurol. 57(5), 773–776 (2005).
   PubMed Web of Science ®Google Scholar
• Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nature Med. 7(4), 393–395 (2001).
   PubMed Web of Science ®Google Scholar
• Wichterle H, Lieberam I, Porter JA, Jessell TM. Directed differentiation of embryonic stem cells into motor neurons. Cell 110(3), 385–397 (2002).
   PubMed Web of Science ®Google Scholar
• Li XJ, Du ZW, Zarnowska ED et al. Specification of motoneurons from human embryonic stem cells. Nature Biotechnol. 23(2), 215–221 (2005).
   PubMed Web of Science ®Google Scholar
• Klein SM, Behrstock S, McHugh J et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum. Gene. Ther. 16(4), 509–521 (2005).
   PubMed Web of Science ®Google Scholar
• Alvarez-Buylla A. Neurogenesis and plasticity in the CNS of adult birds. Exp. Neurol. 115(1), 110–114 (1992).
   PubMed Web of Science ®Google Scholar
• Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J. Neurosci. 22(3), 629–634 (2002).
   PubMed Web of Science ®Google Scholar
• Gage FH. Neurogenesis in the adult brain. J. Neurosci. 22(3), 612–613 (2002).
   PubMed Web of Science ®Google Scholar
• Magavi SS, Macklis JD. Manipulation of neural precursors in situ: induction of neurogenesis in the neocortex of adult mice. Neuropsychopharmacology 25(6), 816–835 (2001).
   PubMed Web of Science ®Google Scholar
• Molyneaux BJ, Arlotta P, Hirata T, Hibi M, Macklis JD. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47(6), 817–831 (2005).
   PubMed Web of Science ®Google Scholar
• Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 45(2), 207–221 (2005).
   PubMed Web of Science ®Google Scholar
• Hand CK, Khoris J, Salachas F et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am. J. Hum. Genet. 70(1), 251–256 (2002).
   PubMed Web of Science ®Google Scholar
• Hosler BA, Siddique T, Sapp PC et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284(13), 1664–1669 (2000).
   PubMed Web of Science ®Google Scholar
• Vance C, Al-Chalabi A, Ruddy D et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain (2006) (In press).
   Google Scholar
• Morita M, Al-Chalabi A, Andersen M et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology (2006) (In press).
   Google Scholar
• Wilhelmsen KC. Disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) is a non-Alzheimer’s frontotemporal dementia. J. Neural. Transm. Suppl. 49, 269–275 (1997).
   PubMedGoogle Scholar
• Hentati A, Ouahchi K, Pericak-Vance MA et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 2(1), 55–60 (1998).
   PubMed Web of Science ®Google Scholar
• Yang Y, Hentati A, Deng HX et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet. 29(2), 160–165 (2001).
   PubMed Web of Science ®Google Scholar
• Blair IP, Bennett CL, Abel A et al. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics 3(1), 1–6 (2000).
   PubMed Web of Science ®Google Scholar