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A small molecule p75NTRligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice

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Simmons, Danielle A., Belichenko, Nadia P., Ford, Ellen C., Semaan, Sarah, Monbureau, Marie, Aiyaswamy, Sruti, Holman, Cameron M., Condon, Christina +3 more·2016·Human Molecular Genetics
DOI 10.1093/hmg/ddw316PMC PMC5418739
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Abstract

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington’s disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

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  • Normalizing p75NTR signaling prevents memory and synaptic deficits in HD mutant mice.

    “Normalizing p75NTR signaling prevented memory and synaptic deficits in HD mutant mice [203,204,205,208].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [208]

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  1. [1]Vonsattel J. Myers R. Stevens T. Ferrante R. Bird E. Richardson E.J. (1985) Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol., 44, 559– 577. 2932539
  2. [2]Walker F.O. (2007) Huntington's disease. Lancet, 369, 218– 228. 17240289
  3. [3]Group HsDCR. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72, 971– 983. 8458085
  4. [4]Zuccato C. Cattaneo E. (2007) Role of brain-derived neurotrophic factor in Huntington's disease. Prog. Neurobiol., 81, 294– 330. 17379385
  5. [5]Gharami K. Xie Y. An J.J. Tonegawa S. Xu B. (2008) Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington's disease phenotypes in mice. J. Neurochem., 105, 369– 379. 18086127 PMC2377033
  6. [6]Reichardt L.F. (2006) Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B. Biol. Sci., 361, 1545– 1564. 16939974 PMC1664664
  7. [7]Roux P.P. Barker P.A. (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol., 67, 203– 233. 12169297
  8. [8]Coulson E.J. Reid K. Murray S.S. Cheema S.S. Bartlett P.F. (2000) Role of neurotrophin receptor p75NTR in mediating neuronal cell death following injury. Clin. Exp. Pharmacol. Physiol., 27, 537– 541. 10874514
  9. [9]Gentry J.J. Barker P.A. Carter B.D. (2004) The p75 neurotrophin receptor: multiple interactors and numerous functions. Prog. Brain Res., 146, 25– 39. 14699954
  10. [10]Ibanez C.F. Simi A. (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci., 35, 431– 440. 22503537
  11. [11]Ma Q. Yang J. Li T. Milner T.A. Hempstead B.L. (2015) Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiol. Dis., 82, 466– 477. 26282324 PMC4819334
  12. [12]Brito V. Puigdellivol M. Giralt A. Del Toro D. Alberch J. Gines S. (2013) Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: implication for neuroprotective therapies. Cell Death Dis., 4, e595. 23598407 PMC3641339
  13. [13]Fortress A.M. Buhusi M. Helke K.L. Granholm A.C. (2011) Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats. J. Aging Res., 2011, 460543. 21785728 PMC3140182
  14. [14]Yoon S.O. Casaccia-Bonnefil P. Carter B. Chao M.V. (1998) Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J. Neurosci., 18, 3273– 3281. 9547236 PMC6792655
  15. [15]Miguez A. Garcia-Diaz Barriga G. Brito V. Straccia M. Giralt A. Gines S. Canals J.M. Alberch J. (2015) Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum. Mol. Genet., 24, 4958– 4970. 26063761
  16. [16]Zuccato C. Marullo M. Conforti P. MacDonald M.E. Tartari M. Cattaneo E. (2008) Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington's disease. Brain Pathol., 18, 225– 238. 18093249 PMC8095509
  17. [17]Plotkin J.L. Day M. Peterson J.D. Xie Z. Kress G.J. Rafalovich I. Kondapalli J. Gertler T.S. Flajolet M. Greengard P., (2014) Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease. Neuron, 83, 178– 188. 24991961 PMC4131293
  18. [18]Simmons D.A. Belichenko N.P. Yang T. Condon C. Monbureau M. Shamloo M. Jing D. Massa S.M. Longo F.M. (2013) A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease. J. Neurosci., 33, 18712– 18727. 24285878 PMC3841443
  19. [19]Brito V. Giralt A. Enriquez-Barreto L. Puigdellivol M. Suelves N. Zamora-Moratalla A. Ballesteros J.J. Martin E.D. Dominguez-Iturza N. Morales M., (2014) Neurotrophin receptor p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction. J. Clin. Invest., 124, 4411– 4428. 25180603 PMC4191006
  20. [20]Bowles K.R. Jones L. (2014) Kinase signalling in Huntington's disease. J. Huntington's Dis., 3, 89– 123. 25062854
  21. [21]Longo F.M. Massa S.M. (2008) Small molecule modulation of p75 neurotrophin receptor functions. CNS Neurol. Disord. Drug Targets, 7, 63– 70. 18289033
  22. [22]Longo F.M. Massa S.M. (2013) Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat. Rev. Drug Discov., 12, 507– 525. 23977697
  23. [23]Massa S.M. Xie Y. Yang T. Harrington A.W. Kim M.L. Yoon S.O. Kraemer R. Moore L.A. Hempstead B.L. Longo F.M. (2006) Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J. Neurosci., 26, 5288– 5300. 16707781 PMC6675309
  24. [24]Yang T. Knowles J.K. Lu Q. Zhang H. Arancio O. Moore L.A. Chang T. Wang Q. Andreasson K. Rajadas J., (2008) Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS One, 3, e3604. 18978948 PMC2575383
  25. [25]Meeker R.B. Poulton W. Clary G. Schriver M. Longo F.M. (2016) Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. Exp. Neurol., 275 Pt 1, 182– 198. PMC4688079 26424436
  26. [27]Meeker R.B. Poulton W. Feng W.H. Hudson L. Longo F.M. (2012) Suppression of Immunodeficiency Virus-Associated Neural Damage by the p75 Neurotrophin Receptor Ligand, LM11A-31, in an In Vitro Feline Model. J. Neuroimmune. Pharmacol., 7, 388– 400. 22161560 PMC3746485
  27. [28]James S.E. Burden H. Burgess R. Xie Y. Yang T. Massa S.M. Longo F.M. Lu Q. (2008) Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology, 29, 605– 612. 18539332 PMC2615238
  28. [29]Friesland A. Weng Z. Duenas M. Massa S.M. Longo F.M. Lu Q. (2014) Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. Neurotoxicology, 45, 81– 90. 25277379 PMC4268328
  29. [30]Shi J. Longo F.M. Massa S.M. (2013) A small molecule p75(NTR) ligand protects neurogenesis after traumatic brain injury. Stem Cells, 31, 2561– 2574. 23940017
  30. [31]Tep C. Lim T.H. Ko P.O. Getahun S. Ryu J.C. Goettl V.M. Massa S.M. Basso M. Longo F.M. Yoon S.O. (2013) Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J. Neurosci., 33, 397– 410. 23303920 PMC3710149
  31. [32]Knowles J.K. Simmons D.A. Nguyen T.V. Vander Griend L. Xie Y. Zhang H. Yang T. Pollak J. Chang T. Arancio O., (2013) A small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol. Aging, 34, 2052– 2063. 23545424 PMC9035212
  32. [33]Nguyen T.V. Shen L. Vander Griend L. Quach L.N. Belichenko N.P. Saw N. Yang T. Shamloo M. Wyss-Coray T. Massa S.M., (2014) Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AbetaPP(L/S) transgenic mice. J. Alzheimer's Dis., 42, 459– 483. 24898660 PMC4278429
  33. [34]Simmons D.A. Knowles J.K. Belichenko N.P. Banerjee G. Finkle C. Massa S.M. Longo F.M. (2014) A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PLoS One, 9, e102136. 25153701 PMC4143160
  34. [35]Kanning K.C. Hudson M. Amieux P.S. Wiley J.C. Bothwell M. Schecterson L.C. (2003) Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J. Neurosci., 23, 5425– 5436. 12843241 PMC6741218
  35. [36]Ceni C. Kommaddi R.P. Thomas R. Vereker E. Liu X. McPherson P.S. Ritter B. Barker P.A. (2010) The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling. J. Cell Sci., 123, 2299– 2307. 20530577
  36. [37]Skeldal S. Matusica D. Nykjaer A. Coulson E.J. (2011) Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling?: Neuronal life, growth and death signalling are crucially regulated by intra-membrane proteolysis and trafficking of p75(NTR). Bioessays, 33, 614– 625. 21717487
  37. [38]Vicario A. Kisiswa L. Tann J.Y. Kelly C.E. Ibanez C.F. (2015) Neuron-type-specific signaling by the p75NTR death receptor is regulated by differential proteolytic cleavage. J. Cell Sci., 128, 1507– 1517. 25720379
  38. [39]Roux P.P. Bhakar A.L. Kennedy T.E. Barker P.A. (2001) The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J. Biol. Chem., 276, 23097– 23104. 11312266
  39. [40]Colin E. Regulier E. Perrin V. Durr A. Brice A. Aebischer P. Deglon N. Humbert S. Saudou F. (2005) Akt is altered in an animal model of Huntington's disease and in patients. Eur. J. Neurosci., 21, 1478– 1488. 15845076
  40. [41]Fan J. Gladding C.M. Wang L. Zhang L.Y. Kaufman A.M. Milnerwood A.J. Raymond L.A. (2012) P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol. Dis., 45, 999– 1009. 22198502
  41. [42]Gianfriddo M. Melani A. Turchi D. Giovannini M.G. Pedata F. (2004) Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow. Neurobiol. Dis., 17, 77– 88. 15350968
  42. [43]Taylor D.M. Moser R. Regulier E. Breuillaud L. Dixon M. Beesen A.A. Elliston L. Silva Santos Mde F. Kim J. Jones L., (2013) MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J. Neurosci., 33, 2313– 2325. 23392662 PMC3711389
  43. [44]Mattson M.P. Meffert M.K. (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ., 13, 852– 860. 16397579
  44. [45]Khoshnan A. Ko J. Watkin E.E. Paige L.A. Reinhart P.H. Patterson P.H. (2004) Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J. Neurosci., 24, 7999– 8008. 15371500 PMC6729796
  45. [46]Trager U. Andre R. Lahiri N. Magnusson-Lind A. Weiss A. Grueninger S. McKinnon C. Sirinathsinghji E. Kahlon S. Pfister E.L., (2014) HTT-lowering reverses Huntington's disease immune dysfunction caused by NFkappaB pathway dysregulation. Brain, 137, 819– 833. 24459107 PMC3983408
  46. [47]Hayden M.S. Ghosh S. (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev., 26, 203– 234. 22302935 PMC3278889
  47. [48]Huxford T. Huang D.B. Malek S. Ghosh G. (1998) The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell, 95, 759– 770. 9865694
  48. [49]Khoshnan A. Patterson P.H. (2011) The role of IkappaB kinase complex in the neurobiology of Huntington's disease. Neurobiol. Dis., 43, 305– 311. 21554955 PMC3124142
  49. [50]Yamashita T. Tucker K.L. Barde Y.A. (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron, 24, 585– 593. 10595511
  50. [51]Yamashita T. Tohyama M. (2003) The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat. Neurosci., 6, 461– 467. 12692556
  51. [52]Bauer P.O. Wong H.K. Oyama F. Goswami A. Okuno M. Kino Y. Miyazaki H. Nukina N. (2009) Inhibition of Rho kinases enhances the degradation of mutant huntingtin. J. Biol. Chem., 284, 13153– 13164. 19278999 PMC2676047
  52. [53]Li M. Huang Y. Ma A.A. Lin E. Diamond M.I. (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol. Dis., 36, 413– 420. 19591939
  53. [54]Narayanan K.L. Chopra V. Rosas H.D. Malarick K. Hersch S. (2015) Rho Kinase Pathway Alterations in the Brain and Leukocytes in Huntington's Disease. Mol. Neurobiol., 53, 2132– 2140. 25941073 PMC4823347
  54. [55]Song W. Volosin M. Cragnolini A.B. Hempstead B.L. Friedman W.J. (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J. Neurosci., 30, 15608– 15615. 21084616 PMC2996105
  55. [56]Yang S. Kim H.M. (2012) The RhoA-ROCK-PTEN pathway as a molecular switch for anchorage dependent cell behavior. Biomaterials, 33, 2902– 2915. 22244698
  56. [57]Koth A.P. Oliveira B.R. Parfitt G.M. Buonocore Jde Q. Barros D.M. (2014) Participation of group I p21-activated kinases in neuroplasticity. J. Physiol. Paris, 108, 270– 277. 25174326
  57. [58]Rex C.S. Chen L.Y. Sharma A. Liu J. Babayan A.H. Gall C.M. Lynch G. (2009) Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol., 186, 85– 97. 19596849 PMC2712993
  58. [59]Schurmann A. Mooney A.F. Sanders L.C. Sells M.A. Wang H.G. Reed J.C. Bokoch G.M. (2000) p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol. Cell. Biol., 20, 453– 461. 10611223 PMC85099
  59. [60]DiFiglia M. Sapp E. Chase K. Davies S. Bates G. Vonsattel J. Aronin N. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science, 277, 1990– 1993. 9302293
  60. [61]Zuccato C. Valenza M. Cattaneo E. (2010) Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol.Rev., 90, 905– 981. 20664076
  61. [62]Pouladi M.A. Morton A.J. Hayden M.R. (2013) Choosing an animal model for the study of Huntington's disease. Nat. Rev. Neurosci., 14, 708– 721. 24052178
  62. [63]Gray M. Shirasaki D.I. Cepeda C. Andre V.M. Wilburn B. Lu X.H. Tao J. Yamazaki I. Li S.H. Sun Y.E., (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci., 28, 6182– 6195. 18550760 PMC2630800
  63. [64]Pouladi M.A. Stanek L.M. Xie Y. Franciosi S. Southwell A.L. Deng Y. Butland S. Zhang W. Cheng S.H. Shihabuddin L.S., (2012) Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice. Hum. Mol.Genet., 21, 2219– 2232. 22328089
  64. [65]Bibb J.A. Yan Z. Svenningsson P. Snyder G.L. Pieribone V.A. Horiuchi A. Nairn A.C. Messer A. Greengard P. (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. Proc. Natl. Acad. Sci. U. S. A, 97, 6809– 6814. 10829080 PMC18747
  65. [66]Bogush A. Pedrini S. Pelta-Heller J. Chan T. Yang Q. Mao Z. Sluzas E. Gieringer T. Ehrlich M.E. (2007) AKT and CDK5/p35 mediate brain-derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro. J. Biol. Chem., 282, 7352– 7359. 17209049
  66. [67]van Dellen A. Welch J. Dixon R.M. Cordery P. York D. Styles P. Blakemore C. Hannan A.J. (2000) N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice. Neuroreport, 11, 3751– 3757. 11117485
  67. [68]Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S., (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87, 493– 506. 8898202
  68. [69]Ferrante R.J. Kowall N.W. Beal M.F. Richardson E.P. Jr. Bird E.D. Martin J.B. (1985) Selective sparing of a class of striatal neurons in Huntington's disease. Science, 230, 561– 563. 2931802
  69. [70]Ferrante R.J. Beal M.F. Kowall N.W. Richardson E.P. Jr. Martin J.B. (1987) Sparing of acetylcholinesterase-containing striatal neurons in Huntington's disease. Brain Res., 411, 162– 166. 2955849
  70. [71]Cicchetti F. Prensa L. Wu Y. Parent A. (2000) Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease. Brain Res. Brain Res. Rev., 34, 80– 101. 11086188
  71. [72]Holley S.M. Joshi P.R. Parievsky A. Galvan L. Chen J.Y. Fisher Y.E. Huynh M.N. Cepeda C. Levine M.S. (2015) Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease. eNeuro, 2, pii: e0008. 26203463 PMC4507822
  72. [73]Deng Y.P. Reiner A. (2016) Cholinergic interneurons in the Q140 knock-in mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input. J Comp. Neurol., Epub ahead of print. doi: 10.1002/cne.24013. PMC5050058 27219491 · DOI
  73. [74]Meade C. Deng Y. Fusco F. Del Mar N. Hersch S. Goldowitz D. Reiner A. (2002) Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice. J. Comp. Neurol., 449, 241– 269. 12115678
  74. [75]Kosinski C.M. Cha J.H. Young A.B. Mangiarini L. Bates G. Schiefer J. Schwarz M. (1999) Intranuclear inclusions in subtypes of striatal neurons in Huntington's disease transgenic mice. Neuroreport, 10, 3891– 3896. 10716229
  75. [76]Farrar A.M. Callahan J.W. Abercrombie E.D. (2011) Reduced striatal acetylcholine efflux in the R6/2 mouse model of Huntington's disease: an examination of the role of altered inhibitory and excitatory mechanisms. Exp. Neurol., 232, 119– 125. 21864528
  76. [77]Smith R. Chung H. Rundquist S. Maat-Schieman M.L. Colgan L. Englund E. Liu Y.J. Roos R.A. Faull R.L. Brundin P., (2006) Cholinergic neuronal defect without cell loss in Huntington's disease. Hum. Mol. Genet., 15, 3119– 3131. 16987871
  77. [78]Vetter J.M. Jehle T. Heinemeyer J. Franz P. Behrens P.F. Jackisch R. Landwehrmeyer G.B. Feuerstein T.J. (2003) Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum. J. Neurochem., 85, 1054– 1063. 12716437
  78. [79]Picconi B. Passino E. Sgobio C. Bonsi P. Barone I. Ghiglieri V. Pisani A. Bernardi G. Ammassari-Teule M. Calabresi P. (2006) Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons. Neurobiol. Dis., 22, 143– 152. 16326108
  79. [80]Jones L. Hughes A. (2011) Pathogenic mechanisms in Huntington's disease. Int. Rev. Neurobiol., 98, 373– 418. 21907095
  80. [81]Parsons M.P. Raymond L.A. (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron, 82, 279– 293. 24742457
  81. [84]Ridley A. Paterson H. Johnston C. Diekmann D. Hall A. (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell, 70, 401– 410. 1643658
  82. [85]Simmons D.A. Casale M. Alcon B. Pham N. Narayan N. Lynch G. (2007) Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia, 55, 1074– 1084. 17551926
  83. [86]Wacker J.L. Huang S.Y. Steele A.D. Aron R. Lotz G.P. Nguyen Q. Giorgini F. Roberson E.D. Lindquist S. Masliah E., (2009) Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. J. Neurosci., 29, 9104– 9114. 19605647 PMC2739279
  84. [87]Franciosi S. Ryu J.K. Shim Y. Hill A. Connolly C. Hayden M.R. McLarnon J.G. Leavitt B.R. (2012) Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol. Dis., 45, 438– 449. 21946335
  85. [88]Mantovani S. Gordon R. Li R. Christie D.C. Kumar V. Woodruff T.M. (2016) Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice. Hum. Mol. Genet., 25, 1780– 1791. 26908618
  86. [90]Ferrante R.J. Kowall N.W. Richardson E.P. Jr. (1991) Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J. Neurosci., 11, 3877– 3887. 1836019 PMC6575286
  87. [91]Graveland G. Williams R. DiFiglia M. (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. Science, 227, 770– 773. 3155875
  88. [92]Heck N. Betuing S. Vanhoutte P. Caboche J. (2012) A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington's disease. Brain Struct. Funct., 217, 421– 434. 21822732
  89. [93]Klapstein G.J. Fisher R.S. Zanjani H. Cepeda C. Jokel E.S. Chesselet M.F. Levine M.S. (2001) Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice. J. Neurophysiol., 86, 2667– 2677. 11731527
  90. [94]Rocher A.B. Gubellini P. Merienne N. Boussicault L. Petit F. Gipchtein P. Jan C. Hantraye P. Brouillet E. Bonvento G. (2016) Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease. Neurobiol. Dis., 86, 131– 139. 26626081
  91. [95]Dougherty K.D. Milner T.A. (1999) p75NTR immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles. J. Comp. Neurol., 407, 77– 91. 10213189
  92. [97]Zagrebelsky M. Holz A. Dechant G. Barde Y.A. Bonhoeffer T. Korte M. (2005) The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J. Neurosci., 25, 9989– 9999. 16251447 PMC6725571
  93. [98]Bolivar V.J. Manley K. Messer A. (2003) Exploratory activity and fear conditioning abnormalities develop early in R6/2 Huntington's disease transgenic mice. Behav. Neurosci., 117, 1233– 1242. 14674843
  94. [99]Carter R. Lione L. Humby T. Mangiarini L. Mahal A. Bates G. Dunnett S. Morton A. (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J. Neurosci., 19, 3248– 3257. 10191337 PMC6782264
  95. [100]Hickey M.A. Gallant K. Gross G.G. Levine M.S. Chesselet M.F. (2005) Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing. Neurobiol. Dis., 20, 1– 11. 16137562
  96. [101]Menalled L. El-Khodor B.F. Patry M. Suarez-Farinas M. Orenstein S.J. Zahasky B. Leahy C. Wheeler V. Yang X.W. MacDonald M., (2009) Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol. Dis., 35, 319– 336. 19464370 PMC2728344
  97. [102]Casaca-Carreira J. Temel Y. van Zelst M. Jahanshahi A. (2015) Coexistence of Gait Disturbances and Chorea in Experimental Huntington's Disease. Behav. Neurol., 2015, 970204. 26063966 PMC4438172
  98. [103]Abada Y.S. Schreiber R. Ellenbroek B. (2012) Motor, emotional and cognitive deficits in adult BACHD mice: A model for Huntington's disease. Behav. Brain Res., 238, 243– 251. 23123142
  99. [104]Grimbergen Y.A. Knol M.J. Bloem B.R. Kremer B.P. Roos R.A. Munneke M. (2008) Falls and gait disturbances in Huntington's disease. Mov. Disord., 23, 970– 976. 18381643
  100. [105]Koller W.C. Trimble J. (1985) The gait abnormality of Huntington's disease. Neurology, 35, 1450– 1454. 3162109
  101. [106]Shu Y.H. Lu X.M. Wei J.X. Xiao L. Wang Y.T. (2015) Update on the role of p75NTR in neurological disorders: A novel therapeutic target. Biomed. Pharmacother., 76, 17– 23. 26653545
  102. [107]Dechant G. Barde Y.A. (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat. Neurosci., 5, 1131– 1136. 12404007
  103. [108]Meeker R.B. Williams K.S. (2015) The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen. Res., 10, 721– 725. 26109945 PMC4468762
  104. [109]Frade J.M. (2005) Nuclear translocation of the p75 neurotrophin receptor cytoplasmic domain in response to neurotrophin binding. J. Neurosci., 25, 1407– 1411. 15703394 PMC6726010
  105. [110]Jung K.M. Tan S. Landman N. Petrova K. Murray S. Lewis R. Kim P.K. Kim D.S. Ryu S.H. Chao M.V., (2003) Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J. Biol. Chem., 278, 42161– 42169. 12913006
  106. [111]Humbert S. Bryson E.A. Cordelieres F.P. Connors N.C. Datta S.R. Finkbeiner S. Greenberg M.E. Saudou F. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell, 2, 831– 837. 12062094
  107. [112]Rangone H. Pardo R. Colin E. Girault J.A. Saudou F. Humbert S. (2005) Phosphorylation of arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced toxicity by rescuing proteasome impairment. J. Biol. Chem., 280, 22021– 22028. 15809304
  108. [113]Zala D. Colin E. Rangone H. Liot G. Humbert S. Saudou F. (2008) Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum. Mol. Genet., 17, 3837– 3846. 18772195
  109. [114]Hensel N. Rademacher S. Claus P. (2015) Chatting with the neighbors: crosstalk between Rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders. Front. Neurosci., 9, 198. 26082680 PMC4451340
  110. [115]Bauer P.O. Nukina N. (2009) Enhanced degradation of mutant huntingtin by rho kinase inhibition is mediated through activation of proteasome and macroautophagy. Autophagy, 5, 747– 748. 19411823
  111. [116]Shao J. Welch W.J. Diprospero N.A. Diamond M.I. (2008) Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. Mol. Cell. Cell. Biol., 28, 5196– 5208. PMC2519718 18573880
  112. [117]Perrin V. Dufour N. Raoul C. Hassig R. Brouillet E. Aebischer P. Luthi-Carter R. Deglon N. (2009) Implication of the JNK pathway in a rat model of Huntington's disease. Exp. Neurol., 215, 191– 200. 19022249
  113. [118]Govek E. Newey S. Van Aelst L. (2005) The role of the Rho GTPases in neuronal development. Genes Dev., 19, 1– 49. 15630019
  114. [119]Nakayama A.Y. Harms M.B. Luo L. (2000) Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci., 20, 5329– 5338. 10884317 PMC6772334
  115. [120]Zhang H. Petit G.H. Gaughwin P.M. Hansen C. Ranganathan S. Zuo X. Smith R. Roybon L. Brundin P. Mobley W.C., (2013) NGF rescues hippocampal cholinergic neuronal markers, restores neurogenesis, and improves the spatial working memory in a mouse model of Huntington's Disease. J. Huntington's Dis., 2, 69– 82. 25063430
  116. [121]Chopra V. Fox J.H. Lieberman G. Dorsey K. Matson W. Waldmeier P. Housman D.E. Kazantsev A. Young A.B. Hersch S. (2007) A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc. Natl Acad. Sci. U. S. A, 104, 16685– 16689. PMC2034257 17925440
  117. [122]Dedeoglu A. Kubilus J.K. Jeitner T.M. Matson S.A. Bogdanov M. Kowall N.W. Matson W.R. Cooper A.J. Ratan R.R. Beal M.F., (2002) Therapeutic effects of cystamine in a murine model of Huntington's disease. J. Neurosci., 22, 8942– 8950. 12388601 PMC6757687
  118. [125]Yamamoto A. Lucas J.J. Hen R. (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell, 101, 57– 66. 10778856
  119. [126]Bokoch G.M. (2003) Biology of the p21-activated kinases. Annu. Rev. Biochem., 72, 743– 781. 12676796
  120. [127]Penzes P. Cahill M.E. (2012) Deconstructing signal transduction pathways that regulate the actin cytoskeleton in dendritic spines. Cytoskeleton, 69, 426– 441. 22307832 PMC3576145
  121. [128]Penzes P. Rafalovich I. (2012) Regulation of the actin cytoskeleton in dendritic spines. Adv. Exp. Med.Biol., 970, 81– 95. 22351052 PMC3576144
  122. [129]Majumdar D. Nebhan C.A. Hu L. Anderson B. Webb D.J. (2011) An APPL1/Akt signaling complex regulates dendritic spine and synapse formation in hippocampal neurons. Mol. Cell. Neurosci., 46, 633– 644. 21236345 PMC3046229
  123. [130]Tashiro A. Yuste R. (2008) Role of Rho GTPases in the morphogenesis and motility of dendritic spines. Methods Enzymol., 439, 285– 302. 18374172
  124. [131]Hong S.L. Cossyleon D. Hussain W.A. Walker L.J. Barton S.J. Rebec G.V. (2012) Dysfunctional behavioral modulation of corticostriatal communication in the R6/2 mouse model of Huntington's disease. PLoS One, 7, e47026. 23056565 PMC3464283
  125. [132]Aosaki T. Graybiel A.M. Kimura M. (1994) Effect of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys. Science, 265, 412– 415. 8023166
  126. [133]Chen J.Y. Wang E.A. Cepeda C. Levine M.S. (2013) Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility. Front. Neurosci., 7, 114. 23847463 PMC3701870
  127. [134]Lawrence A. Hodges J. Rosser A. Kershaw A. French-Constant C. Rubinsztein D. Robbins T. and BJ, S. (1998) Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain Pathol., 121, 1329– 1341. 9679784
  128. [135]Lawrence A.D. Sahakian B.J. Hodges J.R. Rosser A.E. Lange K.W. Robbins T.W. (1996) Executive and mnemonic functions in early Huntington's disease. Brain, 119, 1633– 1645. 8931586
  129. [136]Rao A.K. Muratori L. Louis E.D. Moskowitz C.B. Marder K.S. (2008) Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease. Mov. Disord., 23, 1100– 1107. 18412252
  130. [137]Bylsma F.W. Rothlind J. Hall M.R. Folstein S.E. Brandt J. (1993) Assessment of adaptive functioning in Huntington's disease. Mov. Disord., 8, 183– 190. 8474487
  131. [138]Marder K. Zhao H. Myers R.H. Cudkowicz M. Kayson E. Kieburtz K. Orme C. Paulsen J. Penney J.B. Jr. Siemers E., (2000) Rate of functional decline in Huntington's disease. Huntington Study Group. Neurology, 54, 452– 458. 10668713
  132. [139]Wheelock V.L. Tempkin T. Marder K. Nance M. Myers R.H. Zhao H. Kayson E. Orme C. Shoulson I. Huntington Study G. (2003) Predictors of nursing home placement in Huntington disease. Neurology, 60, 998– 1001. 12654967
  133. [140]Simmons D.A. Mehta R.A. Lauterborn J.C. Gall C.M. Lynch G. (2011) Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice. Neurobiol. Dis., 41, 436– 444. 20977939 PMC3014441
  134. [141]Balci F. Oakeshott S. Shamy J.L. El-Khodor B.F. Filippov I. Mushlin R. Port R. Connor D. Paintdakhi A. Menalled L., (2013) High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease. PLoS Currents, 5, doi: 10.1371/currents.hd.124aa0d16753f88215776fba102ceb29. PMC3710674 23863947 · DOI
  135. [142]Rudenko O. Tkach V. Berezin V. Bock E. (2009) Detection of early behavioral markers of Huntington's disease in R6/2 mice employing an automated social home cage. Behav. Brain Res., 203, 188– 199. 19410605
  136. [143]Franklin K. Paxinos G. (2008) The Mouse Brain in Stereotaxic Coordinates. Elsevier Inc, New York.
  137. [144]Lerner R.P. Trejo Martinez Ldel C. Zhu C. Chesselet M.F. Hickey M.A. (2012) Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease. Brain Res. Bull., 87, 571– 578. 22326483 PMC3319635
  138. [145]Bourne J.N. Harris K.M. (2008) Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci., 31, 47– 67. 18284372 PMC2561948

Cited by

Sorted by citations

Authors
Simmons, D. A., Belichenko, N. P., Ford, E. C., Semaan, S., Monbureau, M., Aiyaswamy, S., Holman, C. M., Condon, C., Shamloo, M., Massa, S. M., & Longo, F. M.
Affiliations
  • Stanford Medicine (US)
  • San Francisco VA Medical Center (US)
Corresponding author
Simmons, Danielle A.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2016-09-16
Volume
25
Issue
22
Pages
ddw316
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddw316
PMC
PMC5418739
OpenAlex
W2518802028
Cited by
46
References
7
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 2 · 2016: 1
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000267)
  • Jean Perkins Foundation
  • National Institutes of Health (1r21ns081089-01a1, R21 NS081089-01, NS069375)
  • National Institute on Aging (P50AG047366)
  • National Institute of Neurological Disorders and Stroke (P30NS069375, R21 NS081089)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Huntington's disease, p75 neurotrophin receptor, LM11A-31, small-molecule ligands, mutant huntingtin, R6/2 mice, BACHD mice, Akt signaling, c-Jun kinase, neurodegeneration, striatal cholinergic interneurons, dendritic spine density, neuroinflammation, motor and cognitive deficits, neuroprotective therapy
MeSH terms
Huntingtin Protein, Animals, Disease Models, Animal, Huntington Disease, Isoleucine, Ligands, Male, Mice, Transgenic, Morpholines, Phenotype, Protein Binding, Random Allocation, Signal Transduction, Receptors, Nerve Growth Factor, Mice, Molecular Targeted Therapy

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