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Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington’s Disease Mice

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Abstract

Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington’s disease (HD). Furthermore, we and others have demonstrated that TrkB/p75NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75NTR expression. Genetic normalization of p75NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75NTR could be promising to prevent motor deficits in HD.

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Abbreviations

A2AR:

adenosine receptor type 2A

BDNF:

brain-derived neurotrophic factor

DARPP32:

dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa

HD:

Huntington’s disease

Htt:

huntingtin

JNK:

c-Jun kinase

KI:

knock-in

PLCγ:

phospholipase C gamma

PDE10A:

phosphodiesterase 10A

mHtt:

mutant huntingtin

MSN:

medium spiny neuron

WT:

wild type

References

  1. Walker FO (2007) Huntington’s disease. Lancet 369:218–228

    CAS  PubMed  Google Scholar 

  2. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Google Scholar 

  3. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EPJ (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577

    CAS  PubMed  Google Scholar 

  4. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993

    CAS  PubMed  Google Scholar 

  5. Ivkovic S, Ehrlich ME (1999) Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. J Neurosci 19:5409–5419

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Baydyuk M, Russell T, Liao G-Y, Zang K, An JJ, Reichardt LF, Xu B (2011) TrkB receptor controls striatal formation by regulating the number of newborn striatal neurons. Proc Natl Acad Sci U S A 108:1669–1674

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM et al (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498

    CAS  PubMed  Google Scholar 

  8. Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME et al (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138

    CAS  PubMed  Google Scholar 

  9. Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5:311–322

    CAS  PubMed  Google Scholar 

  10. Ma Q, Yang J, Li T, Milner TA, Hempstead BL (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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Gharami K, Xie Y, An JJ, 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

    CAS  PubMed  Google Scholar 

  12. Giralt A, Friedman HC, Caneda-Ferron B, Urban N, Moreno E, Rubio N, Blanco J, Peterson A et al (2010) BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington’s disease. Gene Ther 17:1294–1308

    CAS  PubMed  Google Scholar 

  13. Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30:14708–14718

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Simmons DA, Belichenko NP, Yang T, Condon C, Monbureau M, Shamloo M, Jing D, Massa SM et al (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

    CAS  PubMed  Google Scholar 

  15. Gines S, Bosch M, Marco S, Gavalda N, Diaz-Hernandez M, Lucas JJ, Canals JM, Alberch J (2006) Reduced expression of the TrkB receptor in Huntington’s disease mouse models and in human brain. Eur J Neurosci 23:649–658

    PubMed  Google Scholar 

  16. Zuccato C, Marullo M, Conforti P, MacDonald ME, 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

    CAS  PubMed  Google Scholar 

  17. Gines S, Paoletti P, Alberch J (2010) Impaired TrkB-mediated ERK1/2 activation in Huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression. J Biol Chem 285:21537–21548

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liot G, Zala D, Pla P, Mottet G, Piel M, Saudou F (2013) Mutant huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J Neurosci 33:6298–6309

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Plotkin JL, Day M, Peterson JD, Xie Z, Kress GJ, Rafalovich I, Kondapalli J, Gertler TS et al (2014) Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease. Neuron 83:178–188

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nguyen KQ, Rymar VV, Sadikot AF (2016) Impaired TrkB signaling underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington’s disease. Front Cell Neurosci 10:37

    PubMed  PubMed Central  Google Scholar 

  22. Baker SJ, Reddy EP (1996) Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12:1–9

    CAS  PubMed  Google Scholar 

  23. Yamashita T, Tucker KL, Barde YA (1999) Neurotrophin binding to the p75 receptor modulates rho activity and axonal outgrowth. Neuron 24:585–593

    CAS  PubMed  Google Scholar 

  24. Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233

    CAS  PubMed  Google Scholar 

  25. Yamashita T, Tohyama M (2003) The p75 receptor acts as a displacement factor that releases rho from rho-GDI. Nat Neurosci 6:461–467

    CAS  PubMed  Google Scholar 

  26. Yoon SO, Casaccia-Bonnefil P, Carter B, Chao MV (1998) Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J Neurosci 18:3273–3281

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fortress AM, Buhusi M, Helke KL, Granholm A-CE (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

    PubMed  PubMed Central  Google Scholar 

  28. Brito V, Giralt A, Enriquez-Barreto L, Puigdellivol M, Suelves N, Zamora-Moratalla A, Ballesteros JJ, Martin ED et al (2014) Neurotrophin receptor p75(NTR) mediates Huntington’s disease-associated synaptic and memory dysfunction. J Clin Invest 124:4411–4428

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Miguez A, Garcia-Diaz Barriga G, Brito V, Straccia M, Giralt A, Gines S, Canals JM, 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

    CAS  PubMed  Google Scholar 

  30. Simmons DA, Belichenko NP, Ford EC, Semaan S, Monbureau M, Aiyaswamy S, Holman CM, Condon C et al (2016) A small molecule p75NTR ligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice. Hum Mol Genet 25:4920–4938

  31. Puigdellivol M, Cherubini M, Brito V, Giralt A, Suelves N, Ballesteros J, Zamora-Moratalla A, Martin ED et al (2015) A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington’s disease. Hum Mol Genet 24:7265–7285

    PubMed  PubMed Central  Google Scholar 

  32. Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A et al (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington’s disease mice. Proc Natl Acad Sci U S A 97:6809–6814

    CAS  Google Scholar 

  33. Niccolini F, Haider S, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, Natesan S, Piccini P et al (2015) Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease. Brain 138:3016–3029

    PubMed  Google Scholar 

  34. Popoli P, Blum D, Domenici MR, Burnouf S, Chern Y (2008) A critical evaluation of adenosine A2A receptors as potentially “druggable” targets in Huntington’s disease. Curr Pharm Des 14:1500–1511

    CAS  PubMed  Google Scholar 

  35. Spires TL, Grote HE, Garry S, Cordery PM, Van Dellen A, Blakemore C, Hannan AJ (2004) Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington’s disease transgenic mice. Eur J Neurosci 19:2799–2807

    PubMed  Google Scholar 

  36. Murmu RP, Li W, Holtmaat A, Li J-Y (2013) Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington’s disease. J Neurosci 33:12997–13009

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang J, Siao C-J, Nagappan G, Marinic T, Jing D, McGrath K, Chen Z-Y, Mark W et al (2009) Neuronal release of proBDNF. Nat Neurosci 12:113–115

    PubMed  PubMed Central  Google Scholar 

  39. Chapman TR, Barrientos RM, Ahrendsen JT, Hoover JM, Maier SF, Patterson SL (2012) Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol Aging 33:832.e1–832.14

    CAS  Google Scholar 

  40. Calabrese F, Guidotti G, Racagni G, Riva MA (2013) Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor. Neurobiol Aging 34:2768–2776

    CAS  PubMed  Google Scholar 

  41. Zuccato C, Liber D, Ramos C, Tarditi A, Rigamonti D, Tartari M, Valenza M, Cattaneo E (2005) Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery. Pharmacol Res 52:133–139

    CAS  PubMed  Google Scholar 

  42. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389:856–860

    CAS  PubMed  Google Scholar 

  43. Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M (2002) Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36:121–137

    CAS  PubMed  Google Scholar 

  44. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    CAS  PubMed  Google Scholar 

  45. Bowles KR, Jones L (2014) Kinase signalling in Huntington’s disease. J Huntingtons Dis 3:89–123

    CAS  PubMed  Google Scholar 

  46. Saavedra A, Garcia-Martinez JM, Xifro X, Giralt A, Torres-Peraza JF, Canals JM, Diaz-Hernandez M, Lucas JJ et al (2010) PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death Differ 17:324–335

    Google Scholar 

  47. Gines S, Ivanova E, Seong I-S, Saura CA, MacDonald ME (2003) Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington’s disease knock-in striatal cells. J Biol Chem 278:50514–50522

    CAS  PubMed  Google Scholar 

  48. Apostol BL, Simmons DA, Zuccato C, Illes K, Pallos J, Casale M, Conforti P, Ramos C et al (2008) CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice. Mol Cell Neurosci 39:8–20

    CAS  PubMed  Google Scholar 

  49. 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

    CAS  PubMed  Google Scholar 

  50. Taylor DM, Moser R, Regulier E, Breuillaud L, Dixon M, Beesen AA, Elliston L, de Silva Santos M, F et al (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

    CAS  PubMed  Google Scholar 

  51. Bragg RM, Coffey SR, Weston RM, Ament SA, Cantle JP, Minnig S, Funk CC, Shuttleworth DD et al (2017) Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington’s disease. Sci Rep 7:41570

  52. Anglada-Huguet M, Xifro X, Giralt A, Zamora-Moratalla A, Martin ED, Alberch J (2014) Prostaglandin E2 EP1 receptor antagonist improves motor deficits and rescues memory decline in R6/1 mouse model of Huntington’s disease. Mol Neurobiol 49:784–795

    CAS  PubMed  Google Scholar 

  53. Garcia-Diaz Barriga G, Giralt A, Anglada-Huguet M, Gaja-Capdevila N, Orlandi JG, Soriano J, Canals J-M, Alberch J (2017) 7,8-Dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington’s disease mouse model through specific activation of the PLCgamma1 pathway. Hum Mol Genet 26:3144–3160

    PubMed  Google Scholar 

  54. Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P et al (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24:7727–7739

    CAS  PubMed  Google Scholar 

  55. Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, Sotogaku N, Fukuda T et al (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28:10460–10471

    CAS  PubMed  Google Scholar 

  56. Girault J-A (2012) Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol 970:407–429

    CAS  PubMed  Google Scholar 

  57. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM (2013) Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494:238–242

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Diogenes MJ, Fernandes CC, Sebastiao AM, Ribeiro JA (2004) Activation of adenosine A2A receptor facilitates brain-derived neurotrophic factor modulation of synaptic transmission in hippocampal slices. J Neurosci 24:2905–2913

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Fontinha BM, Diogenes MJ, Ribeiro JA, Sebastiao AM (2008) Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine. Neuropharmacology 54:924–933

    CAS  PubMed  Google Scholar 

  60. Sebastiao AM, Assaife-Lopes N, Diogenes MJ, Vaz SH, Ribeiro JA (2011) Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A(2A) receptors and the role of lipid rafts. Biochim Biophys Acta 1808:1340–1349

    CAS  PubMed  Google Scholar 

  61. Svenningsson P, Nishi A, Fisone G, Girault J-A, Nairn AC, Greengard P (2004) DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44:269–296

    CAS  PubMed  Google Scholar 

  62. Fernandez E, Schiappa R, Girault J-A, Le Novere N (2006) DARPP-32 is a robust integrator of dopamine and glutamate signals. PLoS Comput Biol 2:e176

    PubMed  PubMed Central  Google Scholar 

  63. Yger M, Girault J-A (2011) DARPP-32, Jack of all trades… Master of which? Front Behav Neurosci 5:56

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Engmann O, Giralt A, Gervasi N, Marion-Poll L, Gasmi L, Filhol O, Picciotto MR, Gilligan D et al (2015) DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nat Commun 6:10099

  65. Smith GA, Rocha EM, McLean JR, Hayes MA, Izen SC, Isacson O, Hallett PJ (2014) Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington’s disease. Hum Mol Genet 23:4510–4527

    CAS  PubMed  Google Scholar 

  66. Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, Hannan AJ (2004) Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J Neurosci 24:2270–2276

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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

    CAS  PubMed  Google Scholar 

  68. Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, Carter BD (2014) A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. J Biol Chem 289:21205–21216

    PubMed  PubMed Central  Google Scholar 

  69. Gatto RG, Chu Y, Ye AQ, Price SD, Tavassoli E, Buenaventura A, Brady ST, Magin RL et al (2015) Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington’s disease. Hum Mol Genet England 24:5285–5298. https://doi.org/10.1093/hmg/ddv248

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Li J-Y, Conforti L (2013) Axonopathy in Huntington’s disease. Exp Neurol 246:62–71

    PubMed  Google Scholar 

  71. Lee FS, Rajagopal R, Chao MV (2002) Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev 13:11–17

    CAS  PubMed  Google Scholar 

  72. Rajagopal R, Chen Z-Y, Lee FS, Chao MV (2004) Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J Neurosci 24:6650–6658

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Berghuis P, Dobszay MB, Wang X, Spano S, Ledda F, Sousa KM, Schulte G, Ernfors P et al (2005) Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc Natl Acad Sci U S A 102:19115–19120

    CAS  Google Scholar 

  74. Lewis MA, Hunihan L, Franco D, Robertson B, Palmer J, Laurent DRS, Balasubramanian BN, Li Y et al (2006) Identification and characterization of compounds that potentiate NT-3-mediated Trk receptor activity. Mol Pharmacol 69:1396–1404

    CAS  PubMed  Google Scholar 

  75. Vesa J, Kruttgen A, Shooter EM (2000) p75 reduces TrkB tyrosine autophosphorylation in response to brain-derived neurotrophic factor and neurotrophin 4/5. J Biol Chem 275:24414–24420

    CAS  PubMed  Google Scholar 

  76. Sakuragi S, Tominaga-Yoshino K, Ogura A (2013) Involvement of TrkB- and p75(NTR)-signaling pathways in two contrasting forms of long-lasting synaptic plasticity. Sci Rep 3:3185

    PubMed  PubMed Central  Google Scholar 

  77. Bibel M, Hoppe E, Barde YA (1999) Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J 18:616–622

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jang H-J, Yang YR, Kim JK, Choi JH, Seo Y-K, Lee YH, Lee JE, Ryu SH et al (2013) Phospholipase C-gamma1 involved in brain disorders. Adv Biol Regul 53:51–62

  79. Stroppolo A, Guinea B, Tian C, Sommer J, Ehrlich ME (2001) Role of phosphatidylinositide 3-kinase in brain-derived neurotrophic factor-induced DARPP-32 expression in medium size spiny neurons in vitro. J Neurochem 79:1027–1032

    CAS  PubMed  Google Scholar 

  80. Chiang M-C, Lee Y-C, Huang C-L, Chern Y (2005) cAMP-response element-binding protein contributes to suppression of the A2A adenosine receptor promoter by mutant huntingtin with expanded polyglutamine residues. J Biol Chem 280:14331–14340

    CAS  PubMed  Google Scholar 

  81. Horne EA, Dell’Acqua ML (2007) Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression. J Neurosci 27:3523–3534

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhou L, Martinez SJ, Haber M, Jones EV, Bouvier D, Doucet G, Corera AT, Fon EA et al (2007) EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association, and dendritic spine morphology. J Neurosci 27:5127–5138

  83. Kim K, Yang J, Kim E (2010) Diacylglycerol kinases in the regulation of dendritic spines. J Neurochem 112:577–587

    CAS  PubMed  Google Scholar 

  84. Meriin AB, Mabuchi K, Gabai VL, Yaglom JA, Kazantsev A, Sherman MY (2001) Intracellular aggregation of polypeptides with expanded polyglutamine domain is stimulated by stress-activated kinase MEKK1. J Cell Biol 153:851–864

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Cowan KJ, Diamond MI, Welch WJ (2003) Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet 12:1377–1391

    CAS  PubMed  Google Scholar 

  86. Scappini E, Koh T-W, Martin NP, O’Bryan JP (2007) Intersectin enhances huntingtin aggregation and neurodegeneration through activation of c-Jun-NH2-terminal kinase. Hum Mol Genet 16:1862–1871

    CAS  PubMed  Google Scholar 

  87. Morfini GA, You Y-M, Pollema SL, Kaminska A, Liu K, Yoshioka K, Bjorkblom B, Coffey ET, Bagnato C, Han D, Huang C-F, Banker G, Pigino G, et al. Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci. United States; 2009; 12: 864–71. doi: https://doi.org/10.1038/nn.2346.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bauer PO, Wong HK, 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

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bauer PO, Nukina N (2009) Enhanced degradation of mutant huntingtin by rho kinase inhibition is mediated through activation of proteasome and macroautophagy. Autophagy 5:747–748

    CAS  PubMed  Google Scholar 

  90. Li M, Huang Y, Ma AAK, Lin E, Diamond MI (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis 36:413–420

    CAS  PubMed  Google Scholar 

  91. 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

    PubMed  PubMed Central  Google Scholar 

  92. Deogracias R, Yazdani M, Dekkers MPJ, Guy J, Ionescu MCS, Vogt KE, Barde Y-A (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 109:14230–14235

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Di Pardo A, Amico E, Favellato M, Castrataro R, Fucile S, Squitieri F, Maglione V (2014) FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease. Hum Mol Genet 23:2251–2265

    PubMed  Google Scholar 

  94. Pang TYC, Stam NC, Nithianantharajah J, Howard ML, Hannan AJ (2006) Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington’s disease transgenic mice. Neuroscience 141:569–584

    CAS  PubMed  Google Scholar 

  95. Hait NC, Wise LE, Allegood JC, O’Brien M, Avni D, Reeves TM, Knapp PE, Lu J et al (2014) Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci 17:971–980

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Cragnolini AB, Friedman WJ (2008) The function of p75NTR in glia. Trends Neurosci 31:99–104

    CAS  PubMed  Google Scholar 

  97. Cragnolini AB, Huang Y, Gokina P, Friedman WJ (2009) Nerve growth factor attenuates proliferation of astrocytes via the p75 neurotrophin receptor. Glia 57:1386–1392

    PubMed  PubMed Central  Google Scholar 

  98. Han I, You Y, Kordower JH, Brady ST, Morfini GA (2010) Differential vulnerability of neurons in Huntington’s disease: the role of cell type-specific features. J Neurochem England 113:1073–1091. https://doi.org/10.1111/j.1471-4159.2010.06672.x

    Article  CAS  Google Scholar 

  99. Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, Duyao MP, Vrbanac V et al (1999) Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Hum Mol Genet 8:115–122

    CAS  PubMed  Google Scholar 

  100. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y et al (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

    CAS  PubMed  Google Scholar 

  101. Kolbeck R, Bartke I, Eberle W, Barde YA (1999) Brain-derived neurotrophic factor levels in the nervous system of wild-type and neurotrophin gene mutant mice. J Neurochem 72:1930–1938

    CAS  PubMed  Google Scholar 

  102. Grutzendler J, Tsai J, Gan W-B (2003) Rapid labeling of neuronal populations by ballistic delivery of fluorescent dyes. Methods 30:79–85

    CAS  PubMed  Google Scholar 

  103. Lloret A, Dragileva E, Teed A, Espinola J, Fossale E, Gillis T, Lopez E, Myers RH et al (2006) Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington’s disease knock-in mice. Hum Mol Genet 15:2015–2024

    CAS  PubMed  Google Scholar 

  104. Pinto RM, Dragileva E, Kirby A, Lloret A, Lopez E, St Claire J, Panigrahi GB, Hou C et al (2013) Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: genome-wide and candidate approaches. PLoS Genet 9:e1003930

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are very grateful to Ana Lopez and Maria Teresa Muñoz for technical assistance, Dr. Teresa Rodrigo and the staff of the animal care facility (Facultat de Psicologia Universitat de Barcelona), and Dr. Maria Calvo, Anna Bosch, and Elisenda Coll from the Advanced Optical Microscopy Unit from Scientific and Technological Centers from University of Barcelona for their support and advice with confocal technique.

Funding

This work was supported by the Ministerio de Ciencia e Innovación (SAF-2014-57160R to J.A and SAF2015-67474-R; MINECO/FEDER to S.G), the Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and the Cure Huntington’s Disease Initiative (CHDI A-3468).

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Authors and Affiliations

  1. Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciències, Universitat de Barcelona, Barcelona, Spain

    Nuria Suelves, Andrés Miguez, Gerardo García-Díaz Barriga, Albert Giralt, Elena Alvarez-Periel, Jordi Alberch, Silvia Ginés & Verónica Brito

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Nuria Suelves, Andrés Miguez, Gerardo García-Díaz Barriga, Albert Giralt, Elena Alvarez-Periel, Jordi Alberch, Silvia Ginés & Verónica Brito

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Nuria Suelves, Andrés Miguez, Gerardo García-Díaz Barriga, Albert Giralt, Elena Alvarez-Periel, Jordi Alberch, Silvia Ginés & Verónica Brito

  4. Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), University of Salamanca, Salamanca, Spain

    Saray López-Benito & Juan Carlos Arévalo

  5. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

    Saray López-Benito & Juan Carlos Arévalo

Authors
  1. Nuria Suelves
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  2. Andrés Miguez
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  3. Saray López-Benito
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  4. Gerardo García-Díaz Barriga
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  5. Albert Giralt
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  6. Elena Alvarez-Periel
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  7. Juan Carlos Arévalo
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  8. Jordi Alberch
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  9. Silvia Ginés
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  10. Verónica Brito
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Contributions

N.S contributed to the design and carried out the biochemical and immunohistochemical studies, analyzed, interpreted data, and participated in the manuscript draft. A.M contributed to the design and carried out the pharmacological studies in R6/1 mice, analyzed, and interpreted data. S.L.B contributed to the design and carried out the ELISA studies, as well as analyzed and interpreted data. G.G.D.B contributed to the design and carried out the biochemical studies in the R6/1 mice, as well as analyzed and interpreted data. A.G participated in behavioral studies in the KI:p75+/− mice, as well as analyzed and interpreted data. E.A.P carried out immunohistochemistry. J.C.A revised and commented the manuscript. J.A revised and commented the manuscript. S.G contributed to data interpretation, to experimental design, and to the manuscript draft. V.B conceived the study, contributed to the design and carried out behavioral and dendritic spine studies, analyzed and interpreted data, wrote the manuscript, and edited the document. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Verónica Brito.

Ethics declarations

Experimental procedures were approved by the Local Ethical Committee of the University of Barcelona (99/01) and the Generalitat de Catalunya (00/1094), following European (2010/63/UE) and Spanish (RD 1201/2005) regulations for the care and use of laboratory animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

Supplemental Figure 1:

No altered expression of p75NTR and BDNF levels in the cortex of KI mice. Representative immunoblots showing the levels of p75NTR in cortical extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6 months of age (A) and mature BDNF (mBDNF) in cortical extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6, 8 and 10 months of age (B). Tubulin was used as loading control. Histograms represent relative protein levels expressed as percentage of WT values. All data are shown as the mean ± SEM (n= 5-7 mice/genotype/age). Data were analyzed by one-way ANOVA followed by Tukey's test. *P <0.05 compared with WT. (GIF 44 kb)

High Resolution Image (TIF 26704 kb)

Supplemental Figure 2:

Normalization of p75NTR expression in KI mice do not affect dendritic spine density at early disease stages. Representative dendrites of medium spiny neurons from WT, p75+/–, KI, and KI:p75+/– mice at 3 months of age. Scale Bar: 2 μm. Histograms show quantitative analysis of dendritic spine density per micrometer of dendritic length. Data are shown as the mean ± SEM (90–100 dendrites; n= 3–5 animals per genotype). Data were analyzed by one-way ANOVA followed by Tukey's test. (GIF 24 kb)

High Resolution Image (TIF 13509 kb)

Supplemental Figure 3:

Antibody validation for the detection of mBDNF in striatal lysates. Western Blot analysis using Santa Cruz anti-BDNF antibody (N-20, rabbit) (A) or anti-BDNF antibody developed by Icosagen (clone3C1, mouse) (B) in striatal lysates from WT, BDNF+/- and BDNF-/- mice. Recombinant BDNF from Prepotech was used as positive control. (GIF 35 kb)

High Resolution Image (TIF 18821 kb)

Supplemental Figure 4:

CREB phosphorylation is not altered in KI mice along disease progression. Representative immunoblots showing the levels of pCREB (ser133) and CREB with tubulin as loading control in striatal extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6, 8 and 10 months of age. Histograms represent the relative ratios of pCREB/CREB expressed as percentage of WT values. All data are shown as the mean ± SEM (n= 5-7 mice/genotype/age). Data were analyzed by one-way ANOVA followed by Tukey's test. (GIF 39 kb)

High Resolution Image (TIF 18188 kb)

Supplemental Figure 5:

Neuronal death is not detected in KI mice. Representative photomicrographs showing no cleaved Caspase-3 (red) positive-stained cells in WT or KI naïve mice at 8 months of age. Mice which had undergone physical lesion in the corticostriatal region causing cell apoptosis were used as positive control of the immunostaining. Scale Bar: 100 μm. (GIF 181 kb)

High Resolution Image (TIF 26924 kb)

Supplemental Figure 6:

Cortical thickness is not altered by p75NTR levels. (A) Representative photomicrographs showing normal cortical thickness (dashed lines) in WT, p75+/-, KI and KI:p75+/- mice at 8 months of age. Scale Bar: 500 μm. (B) Histogram represents quantification of motor cortex thickness (M1). Data are shown as the mean ± SEM (n=5 mice/group). Data were analyzed by one-way ANOVA followed by Tukey's test. (TIF 26924 kb) (GIF 96 kb)

High Resolution Image (TIF 22083 kb)

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Suelves, N., Miguez, A., López-Benito, S. et al. Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington’s Disease Mice. Mol Neurobiol 56, 935–953 (2019). https://doi.org/10.1007/s12035-018-1126-5

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