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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2011

Open Access 01-12-2011 | Research article

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis

Authors: Wei Zhao, Merina Varghese, Shrishailam Yemul, Yong Pan, Alice Cheng, Paul Marano, Sadiq Hassan, Prashant Vempati, Fei Chen, Xianjuan Qian, Giulio M Pasinetti

Published in: Molecular Neurodegeneration | Issue 1/2011

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Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism.

Results

In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord.

Conclusion

Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.
Appendix
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Literature
1.
Pasinelli P, Brown RH: Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006, 7: 710-723.PubMedCrossRef
2.
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993, 362: 59-62. 10.1038/362059a0.PubMedCrossRef
3.
Mattiazzi M, D'Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G: Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem. 2002, 277: 29626-29633. 10.1074/jbc.M203065200.PubMedCrossRef
4.
Swerdlow RH, Parks JK, Cassarino DS, Trimmer PA, Miller SW, Maguire DJ, Sheehan JP, Maguire RS, Pattee G, Juel VC, Phillips LH, Tuttle JB, Bennett JP, Davis RE, Parker WD: Mitochondria in sporadic amyotrophic lateral sclerosis. Exp Neurol. 1998, 153: 135-142. 10.1006/exnr.1998.6866.PubMedCrossRef
5.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994, 264: 1772-1775. 10.1126/science.8209258.PubMedCrossRef
6.
Bruijn LI, Miller TM, Cleveland DW: Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004, 27: 723-749. 10.1146/annurev.neuro.27.070203.144244.PubMedCrossRef
7.
8.
Manfredi G, Xu Z: Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005, 5: 77-87. 10.1016/j.mito.2005.01.002.PubMedCrossRef
9.
Browne SE, Bowling AC, Baik MJ, Gurney M, Brown RH, Beal MF: Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem. 1998, 71: 281-287.PubMedCrossRef
10.
Bowling AC, Schulz JB, Brown RH, Beal MF: Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1993, 61: 2322-2325. 10.1111/j.1471-4159.1993.tb07478.x.PubMedCrossRef
11.
Fukuchi K, Maruyama H, Takagi Y, Gomi K: Direct proteasome inhibition by clasto-lactacystin beta-lactone permits the detection of ubiquitinated p21(waf1) in ML-1 cells. Biochim Biophys Acta. 1999, 1451: 206-210. 10.1016/S0167-4889(99)00081-6.PubMedCrossRef
12.
Jung C, Higgins CM, Xu Z: Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis. J Neurochem. 2002, 83: 535-545. 10.1046/j.1471-4159.2002.01112.x.PubMedCrossRef
13.
Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF: Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999, 5: 347-350. 10.1038/6568.PubMedCrossRef
14.
Lin J, Handschin C, Spiegelman BM: Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005, 1: 361-370. 10.1016/j.cmet.2005.05.004.PubMedCrossRef
15.
Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM: Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab. 2005, 1: 259-271. 10.1016/j.cmet.2005.03.002.PubMedCrossRef
16.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994, 264: 1772-1775. 10.1126/science.8209258.PubMedCrossRef
17.
Pradat PF, Bruneteau G, Gordon PH, Dupuis L, Bonnefont-Rousselot D, Simon D, Salachas F, Corcia P, Frochot V, Lacorte JM, Jardel C, Coussieu C, Le FN, Lacomblez L, Loeffler JP, Meininger V: Impaired glucose tolerance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010, 11: 166-171. 10.3109/17482960902822960.PubMedCrossRef
18.
Jung C, Higgins CM, Xu Z: A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods. 2002, 114: 165-172. 10.1016/S0165-0270(01)00524-6.PubMedCrossRef
19.
Perlson E, Jeong GB, Ross JL, Dixit R, Wallace KE, Kalb RG, Holzbaur EL: A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci. 2009, 29: 9903-9917. 10.1523/JNEUROSCI.0813-09.2009.PubMedPubMedCentralCrossRef
20.
Tortarolo M, Veglianese P, Calvaresi N, Botturi A, Rossi C, Giorgini A, Migheli A, Bendotti C: Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression. Mol Cell Neurosci. 2003, 23: 180-192. 10.1016/S1044-7431(03)00022-8.PubMedCrossRef
21.
Williamson TL, Cleveland DW: Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999, 2: 50-56. 10.1038/4553.PubMedCrossRef
22.
Ackerley S, Grierson AJ, Banner S, Perkinton MS, Brownlees J, Byers HL, Ward M, Thornhill P, Hussain K, Waby JS, Anderton BH, Cooper JD, Dingwall C, Leigh PN, Shaw CE, Miller CC: p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. Mol Cell Neurosci. 2004, 26: 354-364. 10.1016/j.mcn.2004.02.009.PubMedCrossRef
23.
De VK, Severin F, Van HF, Vancompernolle K, Goossens V, Hyman A, Grooten J: Tumor necrosis factor induces hyperphosphorylation of kinesin light chain and inhibits kinesin-mediated transport of mitochondria. J Cell Biol. 2000, 149: 1207-1214. 10.1083/jcb.149.6.1207.CrossRef
24.
Morfini G, Pigino G, Szebenyi G, You Y, Pollema S, Brady ST: JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci. 2006, 9: 907-916. 10.1038/nn1717.PubMedCrossRef
25.
Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grunblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wullner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR: PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med. 2010, 2: 52ra73-PubMedPubMedCentralCrossRef
26.
Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM: PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol. 2009, 66: 352-361. 10.1001/archneurol.2008.588.PubMedPubMedCentralCrossRef
27.
Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D: Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell. 2006, 127: 59-69. 10.1016/j.cell.2006.09.015.PubMedCrossRef
28.
Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M, Sassone J, Ciammola A, Squitieri F, Beal MF: Impaired PGC-1alpha function in muscle in Huntington's disease. Hum Mol Genet. 2009, 18: 3048-3065. 10.1093/hmg/ddp243.PubMedPubMedCentralCrossRef
29.
Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF: Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2005, 191: 331-336. 10.1016/j.expneurol.2004.10.007.PubMedCrossRef
30.
Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schurmann B, Zimmer A, Heneka MT: The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci. 2005, 25: 7805-7812. 10.1523/JNEUROSCI.2038-05.2005.PubMedCrossRef
31.
Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM: Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006, 281: 21745-21754. 10.1074/jbc.M602909200.PubMedCrossRef
32.
Kelley KA, Ho L, Winger D, Freire-Moar J, Borelli CB, Aisen PS, Pasinetti GM: Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2. Am J Pathol. 1999, 155: 995-1004. 10.1016/S0002-9440(10)65199-1.PubMedPubMedCentralCrossRef
33.
varez-Buylla A, Ling CY, Kirn JR: Cresyl violet: a red fluorescent Nissl stain. J Neurosci Methods. 1990, 33: 129-133. 10.1016/0165-0270(90)90016-9.CrossRef
34.
Brouillet E, Guyot MC, Mittoux V, Altairac S, Conde F, Palfi S, Hantraye P: Partial inhibition of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat. J Neurochem. 1998, 70: 794-805.PubMedCrossRef
35.
Pandey M, Varghese M, Sindhu KM, Sreetama S, Navneet AK, Mohanakumar KP, Usha R: Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease. J Neurochem. 2008, 104: 420-434.PubMed
Metadata
Title
Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis
Authors
Wei Zhao
Merina Varghese
Shrishailam Yemul
Yong Pan
Alice Cheng
Paul Marano
Sadiq Hassan
Prashant Vempati
Fei Chen
Xianjuan Qian
Giulio M Pasinetti
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2011
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-6-51

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