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Reviews

Emerging drug targets in amyotrophic lateral sclerosis

, PhD (Senior Director of Target Advancement) & , PhD (Senior Vice President)
Pages 5-20 | Published online: 17 Dec 2012

Bibliography

  • del Aguila MA, Longstretch WT Jr, McGuire V, Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003;60(5):813-19
  • Lee MK, Cleveland DW. Neurofilament function and dysfunction:involvement in axonal growth and neuronal disease. Curr Opin Cell Biol 1994;6(1):34-40
  • Manetto V, Sternberger NH, Perry G, Phosphorylation of neurofilaments is altered in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1988;47:642-53
  • Itoh T, Sobue G, Ken E, Phosphorylated high molecular weight neurofilament protein in the peripheral motor, sensory and sympathetic neuronal perikarya: system-dependent normal variations and changes in amyotrophic lateral sclerosis and multiple system atrophy. Acta Neuropathol 1992;83(3):240-5
  • Oosthuyse B, Moons L, Storkebaum Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001;28:131-8
  • Shaw PJ, Ince PG, Falkous G, Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 1995;38:691-5
  • Abe K, Pan LH, Watanabe M, Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neurosci Lett 1995;199:152-4
  • Smith RG, Henry YK, Mattson MP, Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann Neurol 1998;44:696-9
  • Durham HD. In: Shaw PJ, Strong MJ, editors. Motor neuron disorders: bluebooks of practical aneurology. Butterworth-Heinemann; Philadelphia: 2003. p. 379-400
  • Wang X, Michaelis EK. Selective vulnerability to oxidative stress in the brain. Front Aging Neurosci 2010;2(12):1-13
  • Batulan Z, Shinder GA, Minotti S, High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 2003;23(13):5789-98
  • Taylor DM, Minotti S, Agar JN, Overexpression of metallothionein protects cultured motor neurons against oxidative stress, but not mutant Cu/Zn-superoxide dismutase toxicity. Neurotoxicology 2004;25:779-92
  • Kiernan D, Kalmar B, Dick JR, Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004;10(4):402-5
  • Arimoclomol clinical trials information. Available from: www.Clinical.Trials.gov [Last accessed 24 October 2012]
  • Williams TS, Day NC, Ince PG, Calcium permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann Neurol 1997;42:200-7
  • Greig A, Donevan SD, Mujtaba TJ, Characterization of the AMPA-activated receptors present on motoneurons. J Neurochem 2000;74:179-91
  • Van Damme P, Van Den BL, Van Houtte E, GluR2-dependent properties of AMPA receptors determines the selective vulnerability of motor neurons to excitotoxicity. J Neurophysiol 2002;88:1279-87
  • Rothstein JD, Van Kammen M, Levey AI, Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;38:73-84
  • Ferraiuolo L, Kirby J, Grierson AJ, Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 2011;7:616-30
  • Carriedo SG, Sensi SL, Yin JH, AMPA exposures induce mitochondrial Ca2+ overload and ROS generation in spinal motor neurons in-vitro. J Neurosci 2000;20:240-50
  • Lautenschlaeger J, Prell T, Grosskreutz J. Endoplasmic reticulum stress and the ER mitochondrdia calcium cycle in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012;13:166-77
  • Arnaudeau S, Kelley WL, Walsh JV, Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J Biol Chem 2001;276:29430-9
  • Brini M, Carafoli E. Calcium pumps in Health and Disease. Physiol Rev 2009;89:1341-78
  • Panov AV, Kubalik N, Zinchenko N, Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology. Am J Physiol Regul Integr Comp Physiol 2011;300:R844-54
  • Lodish HF, Kong N, Wikstrom L. Calcium is required for folding of newly made subunits of the asialoglycoprotein receptor within the endoplasmic reticulum. J Biol Chem 1992;267:12753-60
  • Kuznetsov G, Brostrom MA, Brostrom CO. Demonstration of a calcium requirement for secretory protein processing and export. Differential effects of calcium and dithiothreitol. J Biol Chem 1992;267:3932-9
  • Grosskreutz J, Van Den Bosch L, Keller BU. Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium 2010;47:165-74
  • Ince P, Stout N, Shaw P, Parvalbumin and calbindin D-28K in the human motor system and in motor neuron disease. Neuropathol Appl Neurobiol 1993;19:291-9
  • Alexianu ME, Ho B-K, Mohamed AH, The role of calcium binding proteins in selective motor neuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol 1994;36:846-58
  • Elliott JL, Snider WD. Parvalbumin is a marker of ALS-resistant motor neurons. Neuroreport 1995;6:449-52
  • Shaw PJ, Eggett CJ. Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 2000;247(Suppl):I17-27
  • Roy J, Minotti S, Dong L, Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by post-synaptic calcium-dependent mechanisms. J Neurosci 1998;18:9673-84
  • Hetz C, Thielen P, Matus S, XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 2009;23:2294-306
  • Atkin JD, Farg MA, Walker AK, Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol Dis 2008;30:400-7
  • Ilieva EV, Ayala V, Jove M, Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 2007;30:3111-23
  • Mizoule J, Meldrum B, Mazadier M, 2-amino-6-trifluoromethoxybenzothiazole, a possible antagonist of excitatory amino acid neurotransmission. I. Anticovulsant properties. Neuropharmacology 1985;24:767-83
  • Habib AA, Mitsumoto H. Emerging drugs for amyotrophic lateral sclerosis. Expert Opin Emerg Drugs 2011;16(3):537-58
  • Debono MW, Le Guern J, Canton T, Inhibition by riluzole of electrophysiological responses mediated by rat kainite and NMDA receptors expressed in Xenopus oocytes. J Pharmacol 1993;235:283-9
  • Doble A. The pharmacology and mechanism of action of riluzole. Neurology 1996;47(Suppl4):S233-41
  • Doble A, Hubert JP, Blanchard JC. Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on D-[3H]-aspartate release from cerebellar granule cells. Neurosci Lett 1992;140:251-4
  • Siciliano G, Carlesi C, Pasquali L, Clinical trials for neuroprotection in ALS. CNS Neurol Disord Drug Targets 2010;9(3):305-13
  • Traynor BJ, Bruijn L, Conwit R, Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology 2006;67:20-7
  • Bruijn LI, Cudkowicz M. Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies. Expert Rev Neurother 2006;6:417-28
  • GSK1223249 clinical trials information. Available from: www.Clinical.Trials.gov [Last accessed 17 September 2012]
  • Prinja R, Moore SE, Vinson M, Inhibitor of neurite outgrowth in humans. Nature 2000;403:383-4
  • Oertle T, van der Haar ME, Bandtlow CE, Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci 2003;23(13):5393-406
  • Freund P, Schmidlin E, Wannier T, Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates-re-examination and extension of behavioral data. Eur J Neurosci 2009;29:983-96
  • Jokic N, de Aguilar J-LG, Dimou L, The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep 2006;7:1162-7
  • Pradat P-F, Bruneteau G, de Aguilar J-LG, Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes. Ann Neurol 2007;62:15-20
  • Russell AJ, Hartman JJ, Hinken AC, Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 2012;3:452-6
  • Shefner J, Cedarbaum JM, Cudkowicz ME, Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012;13(5):430-8
  • Schmalbach S, Petri S. Histone deacetylation and motor neuron degeneration. CNS Neurol Disord Drug Targets 2010;9(3):279-84
  • Echaniz-Laguna A, Bousiges O, Loeffler JP, Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases. Curr Med Chem 2008;15:1263-73
  • Yoo Y-E, Ko CP. Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 2011;231:147-59
  • Ryu H, Smith K, Camelo SI, Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem 2005;93:1087-98
  • Petri S, Kiaei M, Kipiani K, Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2006;22:40-9
  • Del Signore SJ, Amante DJ, Kim J, Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amyotroph Lateral Scler 2009;10:85-94
  • Chuang D-M, Leng Y, Marinova Z, Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 2009;32:591-601
  • Cudkowicz ME, Andres PL, Macdonald SA, Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99-106
  • Siddique T, Ajroud-Driss S. Familial ALS, a historical perspective. Acta Myol 2011;30:117-20
  • Lagier-Tourenne C, Polymedidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 2010;19:R46-64
  • Lagier-Tourenne C, Cleveland DW. Rethinking the fuss about TDP-43. Cell 2009;136:1001-4
  • Tollervey JR, Curk T, Rogelj B, Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 2011;14(4):452-8
  • Polymenidou M, Lagier-Tourenne C, Hutt KR, Long pre-mRNA depletion and RNA missplicing contribute to the neuronal vulnerability from loss of TDP-43. Nat Neurosci 2011;14:459-68
  • Da Cruz S, Cleveland DW. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 2011;21:904-19
  • Ling S-C, Albuququerque CP, Han JS, ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. PNAS 2010;107:13318-23
  • Kawauchi J, Mischo H, Braglia P, Budding yeast RNA polymerases I and II employ parallel mechanisms of transcriptional termination. Genes Dev 2008;22:1082-92
  • Skourti-Stathaki K, Proudfoot NJ, Gromak N. Human Senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 2011;42:794-805
  • Skorupa A, King MA, Aparicio IM. Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. J Neurosci 2012;32:5024-38
  • Ticozzi N, Tiloca C, Morelli C, Genetics of familial amyotrophic lateral sclerosis. Arch Ital Biol 2011;149:65-82
  • Boillee S, Velde CV, Cleveland DW. ASL: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006;52:39-59
  • Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 2006;7:710-23
  • Bush AI. Is ALS caused by an altered oxidative activity of mutant superoxide dismutase? Nat Neurosci 2002;5:919
  • Hadano S, Benn SC, Kakuta S, Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum Mol Genet 2006;15:233-50
  • Devon RS, Orban PC, Gerrow K, Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. PNAS 2000;103:9595-600
  • Morotz GN, De Vos KJ, Vagnoni A, Amyotrophic lateral sclerosis-associated mutant VABP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet 2012;21(9):1979-88
  • Ferguson CJ, Lenk GM, Meisler MH. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 2009;18(24):4868-78
  • Nagabhushana A, Chalasani ML, Jain N, Regulation of endocytic trafficking of transferring receptor by optineurin and its impairment by a glaucoma-associated mutant. BMC Cell Biol 2010;11(4):1-19
  • Renton AE, Majounie E, Waite A, A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257-68
  • Polymenidou M, Lagier-Tourenne C, Hutt KR, Misregulated RNA processing in amyotrophic lateral sclerosis. Brain Res 2012;1462:3-15
  • Wu C-H, Fallini C, Ticozzi N, Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012;488:499-505
  • Horrevoets AJG. Profilin-1: an unexpected molecule linking vascular inflammation to the actin cytoskeleton. Circ Res 2007;101:328-30
  • Suetsugu S, Miki H, Takenawa T. The essential role of profilin in the assembly of actin for microspike formation. EMBO J 1998;17:6516-26
  • Daoud H, Dobrzeniecka S, Camu W, Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients. Neurobiol Aging 2012;12: In press
  • Hirai H, Maru Y, Hagiwara K, A novel putative tyrosine kinase receptor encoded by the eph gene. Science 1987;238:1717-20
  • Qin H, Noberini R, Huan X, Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity. J Biol Chem 2010;285:644-54
  • Kao T-J, Law C, Kania A. Eph and ephrin signaling: lessons learned from spinal motor neurons. Semin Cell Dev Biol 2012;23:83-91
  • Chen Y, Fu AKY, Ip NY. Eph receptors at synapses: implications in neurodegenerative diseases. Cell Signal 2012;24:606-11
  • Helmbacher F, Schneider-Maunoury S, Topilko P, Targeting of EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development 2000;127:3313-24
  • Murai KK, Nguyen LN, Irie F, Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat. Neurosci 2003;6:153-60
  • Bourgin C, Murai KK, Richter M, The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol 2007;178:1295-307
  • Van Hoecke A, Schoonaert L, Lemmens R, EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med 2012
  • Noberini R, Koolpe M, Peddibhotla S, Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. 2008;283(43):29461-72
  • Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol 2012;23:51-7
  • Farenc C, Celie PNH, Tensen CP, Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state. FEBS Lett 2011;585:3593-9
  • Oki M, Yamamoto H, Taniguchi H, Overexpression of the receptor-tyrosine kinase EphA4 in human gastric cancers. World J Gastroenterol 2008;14(37):5650-6
  • Goldshmit Y, Spanevello MD, Tajouri S, EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS ONE 2011;6(9):e24636
  • Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 2006;46:113-20
  • Barber SC, Shaw PJ. Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target. Free Radic Biol Med 2010;48:629-41
  • Mimoto T, Miyazaki K, Morimoto N, Impaired antioxydative Keap1/Nrf2 system and the downstream stress protein responses in the motor neuron of ALS model mice. Brain Res 2012;1446:109-18
  • Vargas MR, Johnson DA, Sirkis DW, Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci 2008;28(50):13574-81
  • Neymotin A, Calingasan NY, Willie E, Neuroprotective effect of Nrf2/ARE activators, CDDO-ethylamide and CDDO-trifluoroethylamide in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 2011;51(1):88-96
  • Pergola PE, Raskin P, Toto RD, Bardoxolone methyl and kidney function in CKD with Type 2 diabetes. NEJM 2011;365(4):327-36
  • Bandyopadhyay S, Cookson MR. Evolutionary and functional relationships within the DJ1 superfamily. BMC Evol Biol 2004;4:6
  • Bonifati V, Rizzu P, van Baren MJ, Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256-9
  • Wilson MA. The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxid Redox Signal 2011;15:111-22
  • Canet-Aviles RM, Wilson MA, Miller DW, The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. PNAS 2004;101:9103-8
  • Im JY, Lee KW, Junn E, DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex. Neurosci Res 2010;67:203-8
  • Gorner K, Holtorf E, Waak J, Structural determinants of the C-terminal helix-kink-helix motif essential for protein stability and survival promoting activity of DJ-1. J Biol Chem 2007;282:13680-91
  • Kim YC, Kitaura H, Taira T, Oxidation of DJ-1 dependent cell transformation through direct binding of DJ-1 to PTEN. Int J Oncol 2009;35(6):1331-41
  • Annesi G, Savettieri G, Pugliese P, DJ-1 mutations and Parkinsonism-Dementia-Amyotrophic Lateral Sclerosis complex. Ann Neurol 2005;58:803-7
  • Kaji R, Izumi Y, Adachi Y, Kuzuhara S. ALS-Parkinsonism-Dementia complex of Kii and other related diseases in Japan. Parkinsonism Relat Disord 2012;18S1:S190-1
  • Yamashita S, Mori A, Mita S, DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity. J Neurochem 2010;113:860-70
  • Miyazaki S, Yanagida T, Nunome K, DJ-1 binding compounds prevent stress-induced cell death and movement defect in Parkinson's disease model rats. J Neurochem 2008;105:2418-34
  • Macedo MG, Anar B, Bronner IF, The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes. Hum Mol Genet 2003;12(21):2807-16
  • Alvarez-Castelao B, Munoz C, Sanchez I, Reduced protein stability of human DJ-1/Park7 L166P, linked to autosomal recessive Parkinson disease, is due to direct endoproteolytic cleavage by the proteasome. Biochim Biophys Acta 2012;1823(2):524-33
  • Wilson MA, Collins JL, Hod Y, The 1.1 A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. PNAS 2003;100(16):9256-61
  • Ichijo H, Nishida E, Irie K, Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997;275:90-4
  • Bunkoczi G, Salah E, Filippakopoulos P, Structural and functional characterization of the human protein kinase ASK1. Structure 2007;15:1215-26
  • Saitoh M, Nishitoh H, Fujii M, Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 1998;17(9):2596-606
  • Hu X, Weng Z, Chu CT, Peroxiredoxin-2 protects against 6-Hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade. J Neurosci 2011;31(1):247-61
  • Tobiume K, Matsuzawa A, Takahashi T, ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001;2(3):222-8
  • Nishitoh H, Kadowaki H, Nagai A, ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev 2008;22:1451-64
  • Um JW, Im E, Park J, ASK1 negatively regulates the 26S proteasome. J Biol Chem 2010;285(47):36434-46
  • Cuny GD. Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr Pharm Des 2009;15:3919-39
  • Personal communication from Marc Adler, based on homology modles of ASK2 and ASK3 built on the ASK1 structure 2CLQ
  • Matsuzawa A, Saegusa K, Noguchi T, ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 2005;6(6):587-92
  • Norman P. Evaluation of WO2012003387, Gilead's ASK1 inhibitors. Expert Opin Ther Patents 2012;22(4):455-9
  • Boyault C, Zhang Y, Fritah S, HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 2007;21:2172-81
  • Matthias P, Yoshida M, Khochbin S. HDAC6 a new cellular stress surveillance factor. Cell Cycle 2008;7(1):7-10
  • Li G, Jiang H, Chang M, HDAC6 alpha-tubulin deacetylase: A potential therapeutic target in neurodegenerative diseases. J Neurol Sci 2011;304:1-8
  • Kim SH, Shanware NP, Bowler MJ, Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC-6 mRNA. 2010;285(44):34097-105
  • Yu Z, Sawkar AR, Whalen LJ, Isofogamine- and 2,5-Anhydro-2,5-Imino-D-Glucitol-based Glucocerebrosidase pharmacological chaperones for Gaucher disease intervention. J Med Chem 2007;50(1):94-100
  • Hubbert C, Guardiola A, Shao R, HDAC6 is a microtubule-associated deacetylase. Nature 2002;417:455-8
  • Boyault C, Sadoul K, Pabion M, HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 2007;26:5468-76
  • Zilberman Y, Ballestrem C, Carramusa L, Regulation of microtubule dynamics by inhibition of the tubulin deacetylase HDAC6. J Cell Sci 2009;122:3531-41
  • Rivieccio MA, Brochier C, Willis DE, HDAC6 is a target for protection and regeneration following injury in the nervous system. PNAS 2009;106(46):19599-604
  • d'Ydewalle C, Krishnan J, Chiheb DM, HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med 2011;17(8):968-75
  • Zhang Y, Kwon S, Yamaguchi T, Mice lacking histone deacetylase 6 have hyperphosphorylated tubulin but are viable and develop normally. Mol Cell Biol 2008;28(5):1688-701
  • Butler KV, Kalin J, Brochier C, Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, Tubastatin A. J Am Chem Soc 2010;132(31):10842-6
  • Inks ES, Josey BJ, Jesinkey SR, A novel class of small molecule inhibitors of HDAC6. ACS Chem Biol 2012;7:331-9
  • Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 2006;25:6680-4
  • DiDonato JA, Mercurio F, Karin M. NF-kappaB and the link between inflammation and cancer. Immunol Rev 2012;246:379-400
  • Swarup V, Phaneuf D, Dupre N, Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways. J Exp Med 2011;208(12):2429-47
  • Babu GN, Kumar A, Chandra R, Elevated inflammatory markers in a group of amyotrophic lateral sclerosis patients from northern India. Neurochem Res 2008;33:1145-9
  • Cereda C, Baiocchi C, Bongioanni P, TNF and sTNFR1/2 plasma levels in ALS patients. J Neuroimmunol 2008;194:123-31
  • Poloni M, Facchetti D, Mai R, Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis. Neurosci Lett 2000;287:211-14
  • Ghezzi P, Bernardini R, Giuffrida R, Tumor necrosis factor is increased in the spinal cord of an animal model of motor neuron degeneration. Eur Cytokine Netw 1998;9:139-44
  • Tolosa L, Caraballo-Miralles V, Olmos G, Llado J. TNF-alpha potentiates glutamate-induced spinal cord motoneuron death via NF-kappaB. Mol Cell Neurosci 2011;46:176-86
  • Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 2010;1799:775-87
  • Kwak J-H, Jung J-K, Lee H. Nuclear factor-kappa B inhibitors: a patent review (2006-2010). Expert Opin Ther Patents 2011;21(12):1897-910
  • Schieven GL. The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem 2009;9(11):1038-48
  • Coulthard LR, White DE, Jones DL, p38MAPK: stress responses from molecular mechanisms to therapeutics. Trends Mol Med 2009;15(8):369-79
  • Hu JH, Chernoff K, Pelech S, Protein kinase and protein phosphatase expression in the central nervous system of G93A mSOD over-expressing mice. J Neurochem 2003;85:422-31
  • Tortarolo M, Veglianese P, Calvaresi A, Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression. Mol Cell Neurosci 2003;23:180-92
  • Xu L, Guo Y-S, Liu Y-L, Oxidative stress in immune-mediated motoneuron destruction. Brain Res 2009;1302:225-32
  • Ackerley S, Grierson AJ, Banner S, p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. Mol Cell Neurosci 2004;26:354-64
  • Hu JH, Zhang H, Wagey R, Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. J Neurochem 2003;85:432-42
  • Williamson TL, Cleveland DW. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 1999;2:50-6
  • Morfini GA, Burns M, Binder LI, Axonal transport defects in neurodegenerative diseases. J Neurosci 2009;29(41):12776-86
  • Bosco DA, Morfini G, Karabacak NM, Wild type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 2010;13(11):1396-403
  • Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W. Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1G93A-induced motor neuron death. Neurobiol Dis 2007;26:332-41
  • Stevenson A, Yates DM, Manser C, Riluzole protects against glutamate-induced slowing of neurofilament axonal transport. Neurosci Lett 2009;454:161-4
  • Yasuda S, Tanaka H, Takigami S, Yamagata K. p38 MAP kinase inhibitors as potential therapeutic drugs for neural disease. Cent Nerv Syst Agents Med Chem 2011;11(1):45-59
  • Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem 2010;53:2345-53
  • Bano D, Zanetti F, Mende Y, Nicotera P. Neurodegenerative processes in Huntington's disease. Cell Death Disease 2011;2:e228
  • Ravikumar B, Vacher C, Berger Z, Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington's disease. Nat Genet 2004;36(6):585-95
  • Sarkar S, Peristein EO, Imarisio S, Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol 2007;3(6):331-8
  • Lee B-H, Lee MJ, Park S, Enhancement of proteasome activity by a small-molecule inhibitor of Usp14. Nature 2010;467:179-87
  • Rothstein JD, Patel S, Regan MR, beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-7
  • Ceftriaxone clinical trial information. Available from: www.ClinicalTrials.gov [Last accessed 25 October 2012]
  • Sharma K, Weber C, Bairlein M, Proteomics strategy for quantitative protein interaction profiling in cell extracts. Nat Meth 2009;6(10):741-4
  • Glass JD. New drugs for ALS: how do we get there? Exp Neurol 2012;233(1):112-17

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