Background: Several cellular mechanisms have been proposed to explain the pathogenesis of Huntington's disease (HD), including the lack of striatal brain-derived neurotrophic factor (BDNF). Thus, by preferentially binding to tropomyosin receptor kinase B (TrkB) receptor, BDNF is an important neurotrophin implicated in striatal neuronal survival. Objective: To study the influence of BDNF and TrkB receptors in intracellular signaling pathways and caspase-3 activation in HD striatal cells. Methods: HD mutant knockin and wild-type striatal cells were transduced with preproBDNF or full-length TrkB receptors to analyze BDNF processing, AKT and extracellular signal-regulated kinase (ERK) activation and the activity of caspase-3 in the absence or presence of staurosporine (STS). Results: HD mutant cells transduced with preproBDNF-mCherry (mCh) expressed similar levels of pro- and mature BDNF compared to WT cells, but HD cells released lower levels of pro- and mature BDNF. Despite this, BDNF-mCh overexpression rescued decreased AKT phosphorylation and reduced the caspase-3 activation observed in HD cells. Activated ERK was also enhanced in HD BDNF-mCh/TrkB-eGFP receptor co-cultures. Of relevance, overexpression of TrkB-eGFP in HD cells decreased caspase-3 activation, and stimulation of TrkB-eGFP-transduced mutant cells with recombinant human BDNF reduced both basal and STS-induced caspase-3 activation. Conclusion: The results highlight the importance of BDNF-induced TrkB receptor signaling in rescuing HD-mediated apoptotic features in striatal cells.

Keywords:
Huntingtonߣs disease, Mutant huntingtin, BDNF, TrkB receptors, Caspase-3, Apoptosis
1.
The Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971-983.
2.
Gil JM, Rego AC: Mechanisms of neurodegeneration in Huntington's disease. Eur J Neurosci 2008;27:2803-2820.
3.
Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E: Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003;35:76-83.
4.
Li SH, Li XJ: Huntingtin and its role in neuronal degeneration. Neuroscientist 2004;10:467-475.
5.
Wellington CL, Ellerby LM, Gutekunst CA, Rogers D, Warby S, Graham RK, Loubser O, van Raamsdonk J, Singaraja R, Yang YZ, Gafni J, Bredesen D, Hersch SM, Leavitt BR, Roy S, Nicholson DW, Hayden MR: Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J Neurosci 2002;22:7862-7872.
6.
Canals JM, Checa N, Marco S, Akerud P, Michels A, Perez-Navarro E, Tolosa E, Arenas E, Alberch J: Expression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area. J Neurosci 2001;21:117-124.
7.
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E: Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 2001;293:493-498.
8.
Ma B, Savas JN, Chao MV, Tanese N: Quantitative analysis of BDNF/TrkB protein and mRNA in cortical and striatal neurons using α-tubulin as a normalization factor. Cytometry A 2012;81:704-717.
9.
Ferrer I, Goutan E, Marín C, Rey MJ, Ribalta T: Brain-derived neurotrophic factor in Huntington disease. Brain Res 2000;866:257-261.
10.
Ginés S, Seong IS, Fossale E, Ivanova E, Trettel F, Gusella JF, Wheeler VC, Persichetti F, MacDonald ME: Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum Mol Genet 2003;12:497-508.
11.
Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F: Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004;118:127-138.
12.
Ginés S, Bosch M, Marco S, Gavaldà N, Díaz-Hernández M, Lucas JJ, Canals JM, Alberch J: Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain. Eur J Neurosci 2006;23:649-658.
13.
Ginés S, Paoletti P, Alberch J: Impaired TrkB-mediated ERK1/2 activation in Huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression. J Biol Chem 2010;285:21537-21548.
14.
Zuccato C, Marullo M, Conforti P, MacDonald ME, Tartari M, Cattaneo E: Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington's disease. Brain Pathol 2008;18:225-238.
15.
Chao MV, Rajagopal R, Lee FS: Neurotrophin signalling in health and disease. Clin Sci (Lond) 2006;110:167-173.
16.
Murray PS, Holmes PV: An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus. Int J Pept 2011;2011:654085.
17.
Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C: PI3K/Akt and apoptosis: size matters. Oncogene 2003;22:8983-8998.
18.
Perez-Navarro E, Canudas AM, Akerund P, Alberch J, Arenas E: Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington's disease. J Neurochem 2000;75:2190-2199.
19.
Petridis AK, El Maarouf A: Brain-derived neurotrophic factor levels influence the balance of migration and differentiation of subventricular zone cells, but not guidance to the olfactory bulb. J Clin Neurosci 2011;18:265-270.
20.
Bath KG, Lee FS: Neurotrophic factor control of adult SVZ neurogenesis. Dev Neurobiol 2010;70:339-349.
21.
Petersén A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, Sulzer D: Brain-derived neurotrophic factor inhibits apoptosis and dopamine-induced free radical production in striatal neurons but does not prevent cell death. Brain Res Bull 2001;56:331-335.
22.
Almeida S, Laço M, Cunha-Oliveira T, Oliveira CR, Rego AC: BDNF regulates BIM expression levels in 3-nitropropionic acid-treated cortical neurons. Neurobiol Dis 2009;35:448-456.
23.
Almeida S, Cunha-Oliveira T, Laço M, Oliveira CR, Rego AC: Dysregulation of CREB activation and histone acetylation in 3-nitropropionic acid-treated cortical neurons: prevention by BDNF and NGF. Neurotox Res 2010;17:399-405.
24.
Zuccato C, Valenza M, Cattaneo E: Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol Rev 2010;90:905-981.
25.
Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F, Cattaneo E, MacDonald ME: Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells. Hum Mol Genet 2000;9:2799-2809.
26.
Haubensak W, Narz F, Heumann R, Lessmann V: BDNF-GFP containing secretory granules are localized in the vicinity of synaptic junctions of cultured cortical neurons. J Cell Sci 1998;111:1483-1493.
27.
Watson FL, Heerssen HM, Moheban DB, Lin MZ, Sauvageot CM, Bhattacharyya A, Pomeroy SL, Segal RA: Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J Neurosci 1999;19:7889-7900.
28.
Davis HE, Rosinski M, Morgan JR, Yarmush ML: Charged polymers modulate retrovirus transduction via membrane charge neutralization and virus aggregation. Biophys J 2004;86:1234-1242.
29.
Lessmann V, Brigadski T: Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci Res 2009;65:11-22.
30.
Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA: Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 2001;276:12660-12666.
31.
Teng HK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL: ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 2005;25:5455-5463.
32.
Mowla SJ, Pareek S, Farhadi HF, Petrecca K, Fawcett JP, Seidah NG, Morris SJ, Sossin WS, Murphy RA: Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci 1999;19:2069-2080.
33.
del Toro D, Canals JM, Ginés S, Kojima M, Egea G, Alberch J: Mutant huntingtin impairs the post-Golgi trafficking of brain-derived neurotrophic factor but not its Val66Met polymorphism. J Neurosci 2006;26:12748-12757.
34.
Wu LL, Fan Y, Li S, Li XJ, Zhou XF: Huntingtin-associated protein-1 interacts with pro-brain-derived neurotrophic factor and mediates its transport and release. J Biol Chem 2010;285:5614-5623.
35.
Klein R, Conway D, Parada LF, Barbacid M: The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 1990;61:647-656.
36.
Middlemas DS, Lindberg RA, Hunter T: TrkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 1991;11:143-153.
37.
Stoilov P, Castren E, Stamm S: Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun 2002;290:1054-1065.
38.
Haapasalo A, Koponen E, Hoppe E, Wong G, Castrén E: Truncated trkB.T1 is dominant negative inhibitor of trkB.TK+-mediated cell survival. Biochem Biophys Res Commun 2001;280:1352-1358.
39.
Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F: The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt. Dev Cell 2002;2:831-837.
40.
Lopes C, Ribeiro M, Duarte AI, Humbert S, Saudou F, Pereira de Almeida L, Hayden M, Rego AC: IGF-1 Intranasal Administration Rescues Huntington's Disease Phenotypes in YAC128 Mice. Mol Neurobiol 2014;49:1126-1142.
41.
Naia L, Ferreira IL, Cunha-Oliveira T, Duarte AI, Ribeiro M, Rosenstock TR, Laço MN, Ribeiro MJ, Oliveira CR, Saudou F, Humbert S, Rego AC: Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's disease human lymphoblasts. Mol Neurobiol 2015;51:331-348.
42.
Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC: Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells. Free Radic Biol Med 2014;74C:129-144.
43.
Ginés S, Ivanova E, Seong IS, Saura CA, MacDonald ME: 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 2003;278:50514-50522.
44.
Colin E, Régulier E, Perrin V, Dürr A, Brice A, Aebischer P, Déglon N, Humbert S, Saudou F: Akt is altered in an animal model of Huntington's disease and in patients. Eur J Neurosci 2005;21:1478-1488.
45.
Bachelder RE, Ribick MJ, Marchetti A, Falcioni R, Soddu S, Davis KR, Mercurio AM: p53 inhibits α6β4 integrin survival signaling by promoting the caspase 3-dependent cleavage of Akt/PKB. J Cell Biol 1999;147:1063-1072.
46.
François F, Grimes ML: Phosphorylation-dependent Akt cleavage in neural cell in vitro reconstitution of apoptosis. J Neurochem 1999;73:1773-1776.
47.
Rokudai S, Fujita N, Hashimoto Y, Tsuruo T: Cleavage and inactivation of antiapoptotic Akt/PKB by caspases during apoptosis. J Cell Physiol 2000;182:290-296.
48.
Rosenstock TR, de Brito OM, Lombardi V, Louros S, Ribeiro M, Almeida S, Ferreira IL, Oliveira CR, Rego AC: FK506 ameliorates cell death features in Huntington's disease striatal cell models. Neurochem Int 2011;59:600-609.
49.
Ribeiro M, Silva AC, Rodrigues J, Naia L, Rego AC: Oxidizing effects of exogenous stressors in Huntington's disease knock-in striatal cells-protective effect of cystamine and creatine. Toxicol Sci 2013;136:487-499.
50.
Ji Y, Pang PT, Feng L, Lu B: Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat Neurosci 2005;8:164-672.
51.
Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L, Duan S, Lu B: Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010;13:302-309.
52.
Haapasalo A, Sipola I, Larsson K, Akerman KE, Stoilov P, Stamm S, Wong G, Castren E: Regulation of TRKB surface expression by brain-derived neurotrophic factor and truncated TRKB isoforms. J Biol Chem 2002;277:43160-43167.
53.
Chen ZY, Ieraci A, Tanowitz M, Lee FS: A novel endocytic recycling signal distinguishes biological responses of Trk neurotrophin receptors. Mol Biol Cell 2005;16:5761-5772.
54.
Han BH, Holtzman DM: BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000;20:5775-5781.
55.
Wu ZL, O'Kane TM, Scott RW, Savage MJ, Bozyczko-Coyne D: Protein tyrosine phosphatases are up-regulated and participate in cell death induced by polyglutamine expansion. J Biol Chem 2002;277:44208-44213.
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2015
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