Dopamine and α-synuclein dysfunction in Smad3 null mice

Molecular Neurodegeneration

Amelia Sánchez-Capelo²  Xiao-Fan Wang¹  M Ángeles Mena²  M José Casarejos²  M Isabel Cuartero²  Rosa M Giráldez-Pérez²  Silvia Tapia-González² 

[1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA;Centro de Investigaciones Biomédicas en Red - Enfermedades Neurodegenerativas (CIBERNED), Spain

关键词: MAPK;    MAO-B;    α-Synuclein;    TGF-β;    Astrocytes;    Dopamine;    Synucleinopathy;    Parkinson's disease;    Smad3;   

Others  :  865558
DOI  :  10.1186/1750-1326-6-72

 received in 2011-04-13, accepted in 2011-10-13,  发布年份 2011

【 摘 要 】

Background

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-β1 (TGF-β1) levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade.

Results

Striatal monoamine oxidase (MAO)-mediated dopamine (DA) catabolism to 3,4-dihydroxyphenylacetic acid (DOPAC) is strongly increased, promoting oxidative stress that is reflected by an increase in glutathione levels. Fewer astrocytes are detected in the ventral midbrain (VM) and striatal matrix, suggesting decreased trophic support to dopaminergic neurons. The SN of these mice has dopaminergic neuronal degeneration in its rostral portion, and the pro-survival Erk1/2 signalling is diminished in nigra dopaminergic neurons, not associated with alterations to p-JNK or p-p38. Furthermore, inclusions of α-synuclein are evident in selected brain areas, both in the perikaryon (SN and paralemniscal nucleus) or neurites (motor and cingulate cortices, striatum and spinal cord). Interestingly, these α-synuclein deposits are detected with ubiquitin and P^S129-α-synuclein in a core/halo cellular distribution, which resemble those observed in human Lewy bodies (LB).

Conclusions

Smad3 deficiency promotes strong catabolism of DA in the striatum (ST), decrease trophic and astrocytic support to dopaminergic neurons and may induce α-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in α-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents.

【 授权许可】

   
2011 Tapia-González et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Wise RA: Roles for nigrostriatal--not just mesocorticolimbic--dopamine in reward and addiction. Trends Neurosci 2009, 32:517-524.
• [2]Sulzer D: Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease. Trends Neurosci 2007, 30:244-250.
• [3]Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, Brook GA: TGF-beta1 and TGF-beta2 expression after traumatic human spinal cord injury. Spinal Cord 2008, 46:364-371.
• [4]Ilzecka J, Stelmasiak Z, Dobosz B: Transforming growth factor-beta 1 (TGF-beta 1) in patients with amyotrophic lateral sclerosis. Cytokine 2002, 20:239-243.
• [5]Krupinski J, Kumar P, Kumar S, Kaluza J: Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 1996, 27:852-857.
• [6]Li XF, Miyajima M, Jiang CL, Arai H: Expression of TGF-beta s and TGF-beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neurosci Lett 2007, 413:141-144.
• [7]Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T: Transforming growth factor-beta-1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease. Neurosci. Lett 1995, 193:129-132.
• [8]Peress NS, Perillo E: Differential expression of TGF-beta-1, TGF-beta-2 and TGF-beta-3 isotypes in Alzheimer's disease - a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. J Neuropathol Exp Neurol 1995, 54:802-811.
• [9]van der Wal EA, Gómez-Pinilla F, Cotman CW: Transforming Growth Factor-Beta-1 Is in Plaques in Alzheimer and Down Pathologies. Neuroreport 1993, 4:69-72.
• [10]Vawter MP, Dillon-Carter O, Tourtellotte WW, Carvey P, Freed WJ: TGF beta 1 and TGF beta 2 concentrations are elevated in Parkinson's disease in ventricular cerebrospinal fluid. Exp. Neurol 1996, 142:313-322.
• [11]Sánchez-Capelo A: Dual role for TGF-beta 1 in apoptosis. Cytokine Growth Factor Rev 2005, 16:15-34.
• [12]Kalinovsky A, Scheiffele P: Transcriptional control of synaptic differentiation by retrograde signals. Curr Opin Neurobiol 2004, 14:272-279.
• [13]Sanyal S, Kim SM, Ramaswami M: Retrograde regulation in the CNS: Neuron-specific interpretations of TGF-beta signaling. Neuron 2004, 41:845-848.
• [14]Zhang F, Endo S, Cleary LJ, Eskin A, Byrne JH: Role of transforming growth factor-beta in long-term synaptic facilitation in Aplysia. Science 1997, 275:1318-1320.
• [15]Zhang JS, Pho V, Bonasera SJ, Holtzman J, Tang AT, Hellmuth J, Tang SW, Janak PH, Tecott LH, Huang EJ: Essential function of HIPK2 in TGF beta-dependent survival of midbrain dopamine neurons. Nat Neurosci 2007, 10:77-86.
• [16]Krieglstein K, Richter S, Farkas L, Schuster N, Dunker N, Oppenheim RW, Unsicker K: Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death. Nat Neurosci 2000, 3:1085-1090.
• [17]Sánchez-Capelo A, Colin P, Guibert B, Biguet NF, Mallet J: Transforming growth factor beta 1 overexpression in the nigrostriatal system increases the dopaminergic deficit of MPTP mice. Mol Cell Neurosci 2003, 23:614-625.
• [18]Sánchez-Capelo A, Corti O, Mallet J: Adenovirus-mediated over-expression of TGF beta 1 in the striatum decreases dopaminergic cell survival in embryonic nigral grafts. Neuroreport 1999, 10:2169-2173.
• [19]Datto MB, Frederick JP, Pan LH, Borton AJ, Zhuang Y, Wang XF: Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 1999, 19:2495-2504.
• [20]Tatton WG, Chalmers-Redman R, Brown D, Tatton N: Apoptosis in Parkinson's disease: Signals for neuronal degradation. Ann Neurol 2003, 53:S61-S70.
• [21]Cohen G, Farooqui R, Kesler N: Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 1997, 94:4890-4894.
• [22]Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, Nicholls DG, Di Monte DA, Macarthur H, Andersen JK: MAO-B elevation in mouse brain astrocytes results in Parkinson's pathology. PLOS One 2008, 3(2):e1616.
• [23]Damier P, Kastner A, Agid Y, Hirsch EC: Does monoamine oxidase type B play a role in dopaminergic nerve cell death in Parkinson's disease? Neurology 1996, 46:1262-1269.
• [24]Feng XH, Derynck R: Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 2005, 21:659-693.
• [25]Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, Flavell RA: JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 2004, 101:665-670.
• [26]Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T: Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 1998, 152:879-884.
• [27]Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Gitano A, Hikawa R, Tomimoto H, Noda M, Takanashi M, Mori H, Hattori N, Miyakawa T, Kinoshita M: Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 2007, 53:519-533.
• [28]Knerlich-Lukoschus F, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J: Chemokine expression in the white matter spinal cord precursor niche after force-defined spinal cord contusion injuries in adult rats. Glia 2010, 58:916-931.
• [29]Oueslati A, Fournier M, Lashuel HA: Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein: implications for Parkinson's disease pathogenesis and therapies. In Progress in Brain Research. Volume 183, chapter 7. Edited by Anders Björklund, M Angela Cenci. Academic Press; :115-145.
• [30]Yang YC, Piek E, Zavadil J, Liang D, Xie D, Heyer J, Pavlidis P, Kucherlapati R, Roberts AB, Böttinger EP: Hierarchical model of gene regulation by transforming growth factor beta. Proc Natl Acad Sci USA 2003, 100:10269-10274.
• [31]Zhang YE: Non-Smad TGF-beta Signaling Pathways. In The TGF-β Family. Edited by Derynck R, Miyazono K. New York: CSHLP; 2007:419-437.
• [32]Zhu JH, Guo FL, Shelburne J, Watkins S, Chu CT: Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 2003, 13:473-481.
• [33]Zode GS, Sethi A, Brun-Zinkernagel AM, Chang IF, Clark AF, Wordinger RJ: Transforming growth factor-β2 increases extracellular matrix proteins in optic nerve head cells via activation of the Smad signaling pathway. Mol Vision 2011, 17:1745-1758.
• [34]Hamby ME, Hewett JA, Hewett SJ: Smad3-dependent signaling underlies the TGF-β1-mediated enhancement in astrocytic iNOS expression. Glia 2010, 58:1282-1291.
• [35]Zhang Y, Zhang J, Navrazhina K, Argaw AT, Zameer A, Gurfein BT, Brosnan CF, John GR: TGFbeta1 induces Jagged1 expression in astrocytes via ALK5 and Smad3 and regulates the balance between oligodendrocyte progenitor proliferation and differentiation. Glia 2010, 58:964-974.
• [36]Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF: Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. Journal of Biologycal Chemistry 1999, 274:35053-35058.
• [37]Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A: Astroglia in dementia and Alzheimer's disease. Cell Death Diff 2009, 16:378-385.
• [38]Zigmond MJ, Hastings TG, Perez RG: Increased dopamine turnover after partial loss of dopaminergic neurons: compensation or toxicity? Parkinsonism Relat Disord 2002, 8:389-393.
• [39]Schapira AH: Future directions in the treatment of Parkinson's disease. Mov Disord 2007, (Suppl 17):S385-391.
• [40]Eriksen JL, Przedborski S, Petrucelli L: Gene dosage and pathogenesis of Parkinson's disease. Trends Mol Med 2005, 11:91-96.
• [41]Kahle PJ, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C: Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001, 159:2215-2225.
• [42]Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997, 388:839-840.
• [43]Burke WJ, Kumar V, Pandey N, Panneton WM, Gan Q, Franko MW, O'Dell M, Li SW, Pan Y, Chung HD, Galvin JE: Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol 2008, 115:193-203.
• [44]Halliday GM, McCann H: Human-based studies on alpha-synuclein deposition and relationship to Parkinson's disease symptoms. Exp Neurol 2008, 209:12-21.
• [45]Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E: Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003, 24:197-211.
• [46]Brooks DJ: Examining Braak's hypothesis by imaging Parkinson's disease. Mov Disord 2010, 25(Suppl 1):S83-88.
• [47]Lang A: Parkinsonism. In Cecil Medicine. Volume chap 433. 23rd edition. Edited by Goldman L, Ausiello D. Philadelphia: Saunders Elsevier; 2007.
• [48]Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J: Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003, 278:43628-43635.
• [49]Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J: Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 2003, 12:2277-91.
• [50]Perez FA, Palmiter RD: Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 2005, 102:2174-2179.
• [51]Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J: Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 2005, 45:489-496.
• [52]Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J: Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA 2007, 104:11441-11446.
• [53]Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A: Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000, 25:239-252.
• [54]Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL: Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 2002, 22:8797-8807.
• [55]Gitler AD, Shorter J: Prime time for alpha-synuclein. J Neurosci 2007, 27:2433-2434.
• [56]Zeiss CJ: Neuroanatomical phenotyping in the mouse: the dopaminergic system. Vet Pathol 2005, 42:753-773.
• [57]Paxinos G, Franklin K: The mouse brain in stereotaxic coordinates, Compact. third edition. London: Academic Press; 2007.
• [58]West MJ, Slomianka L, Gundersen HJ: Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 1991, 231:482-497.
• [59]German DC, Nelson EL, Liang CL, Speciale SG, Sinton CM, Sonsalla PK: The neurotoxin MPTP causes degeneration of specific nucleus A8, A9 and A10 dopaminergic neurons in the mouse. Neurodegeneration 1996, 5:299-312.
• [60]Machida H, Ogawa K, Funaba M, Mizutani T, Tsujimoto M: mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5-5.fl. Eur J Endocrinol 2000, 143:705-710.
• [61]Mena MA, Garcia de Yebenes MJ, Tabernero C, Casarejos MJ, Pardo B, Garcia de Yebenes J: Effects of calcium antagonists on the dopamine system. Clin Neuropharmacol 1995, 18:410-426.
• [62]Tietze F: Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione: application to mammalian blood and other tissue. Anal Biochem 1969, 27:502-522.
• [63]Griffith OW: Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal Biochem 1980, 106:207-212.