VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models

Orphanet Journal of Rare Diseases

Faraz Farooq¹  Alex MacKenzie¹  Martin Holcik¹  Kevin Mongeon¹  Fahad Shamim¹  Duncan MacKenzie¹  Jeremiah Hadwen¹ 

[1] Children’s Hospital of Eastern Ontario Research Institute, Apoptosis Research Centre, 401 Smyth Road, Ottawa Ontario K1H 8L1, Canada

关键词: Therapeutics;    VPAC2 receptor agonist;    SMA;    SMN;    p38 pathway;   

Others  :  863325
DOI  :  10.1186/1750-1172-9-4

 received in 2013-11-13, accepted in 2014-01-03,  发布年份 2014

【 摘 要 】

Background

Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA.

Methods and results

Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models.

Conclusion

Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target.

【 授权许可】

   
2014 Hadwen et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA, Allitto BA: Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Gen 2012, 20:27-32.
• [2]D’Amico A, Mercuri E, Tiziano FD, Bertini E: Spinal muscular atrophy. Orphanet J Rare Dis 2011, 6:71. BioMed Central Full Text
• [3]Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M: Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995, 80:155-165.
• [4]Lorson CL, Hahnen E, Androphy EJ, Wirth B: A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999, 96:6307-6311.
• [5]Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD: A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999, 8:1177-1183.
• [6]Farooq F, Balabanian S, Liu X, Holcik M, MacKenzie A: p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum Mol Genet 2009, 18:4035-4045.
• [7]Farooq F, Abadia-Molina F, MacKenzie D, Hadwen J, Shamim F, O’Reilly S, Holcik M, MacKenzie A: Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation. Hum Mol Genet 2013, 22:3415-3424.
• [8]Garry EM, Delaney A, Blackburn-Munro G, Dickinson T, Moss A, Nakalembe I, Robertson DC, Rosie R, Robberecht P, Mitchell R, Fleetwood-Walker SM: Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci 2005, 30:523-537.
• [9]Monaghan TK, Mackenzie CJ, Plevin R, Lutz EM: PACAP-38 induces neuronal differentiation of human SH-SY5Y neuroblastoma cells via cAMP-mediated activation of ERK and p38 MAP kinases. J Neurochem 2008, 104:74-88.
• [10]Avila AM, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P, Cizman Z, Di Prospero NA, Pellizzoni L, Fischbeck KH, Sumner CJ: Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest 2007, 117:659-671.
• [11]Riessland M, Ackermann B, Forster A, Jakubik M, Hauke J, Garbes L, Fritzsche I, Mende Y, Blumcke I, Hahnen E, Wirth B: SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum Mol Genet 2010, 19:1492-1506.
• [12]Brook M, Sully G, Clark AR, Saklatvala J: Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett 2000, 483:57-61.
• [13]Dean JL, Brook M, Clark AR, Saklatvala J: p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 1999, 274:264-269.
• [14]Frevel MA, Bakheet T, Silva AM, Hissong JG, Khabar KS, Williams BR: p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. Mol Cell Biol 2003, 23:425-436.
• [15]Rutault K, Hazzalin CA, Mahadevan LC: Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha ) mRNA induction. Evidence for selective destabilization of TNF-alpha transcripts. J Biol Chem 2001, 276:6666-6674.
• [16]Wang SW, Pawlowski J, Wathen ST, Kinney SD, Lichenstein HS, Manthey CL: Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase. Inflamm Res 1999, 48:533-538.
• [17]Legos JJ, Erhardt JA, White RF, Lenhard SC, Chandra S, Parsons AA, Tuma RF, Barone FC: SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res 2001, 892:70-77.
• [18]Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GJ, Burghes AH: SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 2005, 14:845-857.
• [19]Basille M, Cartier D, Vaudry D, Lihrmann I, Fournier A, Freger P, Gallo-Payet N, Vaudry H, Gonzalez B: Localization and characterization of pituitary adenylate cyclase-activating polypeptide receptors in the human cerebellum during development. J Comp Neurol 2006, 496:468-478.
• [20]Harmar AJ, Sheward WJ, Morrison CF, Waser B, Gugger M, Reubi JC: Distribution of the VPAC2 receptor in peripheral tissues of the mouse. Endocrinology 2004, 145:1203-1210.
• [21]Kalamatianos T, Kallo I, Piggins HD, Coen CW: Expression of VIP and/or PACAP receptor mRNA in peptide synthesizing cells within the suprachiasmatic nucleus of the rat and in its efferent target sites. J Comp Neurol 2004, 475:19-35.
• [22]Reubi JC: In vitro evaluation of VIP/PACAP receptors in healthy and diseased human tissues. Clinical implications. Ann N Y Acad Sci 2000, 921:1-25.
• [23]Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA: Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res 2000, 60:3105-3112.
• [24]Schulz S, Rocken C, Mawrin C, Weise W, Hollt V, Schulz S: Immunocytochemical identification of VPAC1, VPAC2, and PAC1 receptors in normal and neoplastic human tissues with subtype-specific antibodies. Clin Cancer Res 2004, 10:8235-8242.
• [25]Sherwood NM, Krueckl SL, McRory JE: The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 2000, 21:619-670.
• [26]Millino C, Fanin M, Vettori A, Laveder P, Mostacciuolo ML, Angelini C, Lanfranchi G: Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy. BMC Med 2009, 7:14. BioMed Central Full Text
• [27]Farooq F, Molina FA, Hadwen J, MacKenzie D, Witherspoon L, Osmond M, Holcik M, MacKenzie A: Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. J Clin Invest 2011, 121:3042-3050.
• [28]Araujo A, Araujo M, Swoboda KJ: Vascular perfusion abnormalities in infants with spinal muscular atrophy. J Pediatr 2009, 155:292-294.
• [29]Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH, Kaspar BK: Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet 2010, 19:3895-3905.
• [30]Bowerman M, Swoboda KJ, Michalski JP, Wang GS, Reeks C, Beauvais A, Murphy K, Woulfe J, Screaton RA, Scott FW, Kothary R: Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol 2012, 72:256-268.
• [31]Gogliotti RG, Quinlan KA, Barlow CB, Heier CR, Heckman CJ, Didonato CJ: Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci 2012, 32:3818-3829.
• [32]Heier CR, Satta R, Lutz C, DiDonato CJ: Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 2010, 19:3906-3918.
• [33]Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR: Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011, 478:123-126.
• [34]Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, Xu X, Davis C, Wooley J, Goldhamer DJ, et al.: Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci 2012, 32:8703-8715.
• [35]Rudnik-Schoneborn S, Vogelgesang S, Armbrust S, Graul-Neumann L, Fusch C, Zerres K: Digital necroses and vascular thrombosis in severe spinal muscular atrophy. Muscle Nerve 2010, 42:144-147.
• [36]Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL: Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet 2010, 19:4059-4071.
• [37]Pan CQ, Li F, Tom I, Wang W, Dumas M, Froland W, Yung SL, Li Y, Roczniak S, Claus TH, et al.: Engineering novel VPAC2-selective agonists with improved stability and glucose-lowering activity in vivo. J Pharmacol Exp Ther 2007, 320:900-906.
• [38]Tsutsumi M, Claus TH, Liang Y, Li Y, Yang L, Zhu J, Dela Cruz F, Peng X, Chen H, Yung SL, et al.: A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes. Diabetes 2002, 51:1453-1460.
• [39]Darsalia V, Mansouri S, Wolbert P, Barde S, Sjoholm A, Patrone C: The specific VPAC2 agonist Bay 55-9837 increases neuronal damage and hemorrhagic transformation after stroke in type 2 diabetic rats. Neuropeptides 2012, 47:133-137.