Rapamycin increases survival in ALS mice lacking mature lymphocytes

Molecular Neurodegeneration

Ludo Van Den Bosch³  Wim Robberecht²  Adrian Liston¹  Philip Van Damme²  James Dooley¹  André Bento-Abreu³  Susann Schönefeldt¹  Sara Hernandez³  Kim A Staats¹ 

[1] Department of Microbiology and Immunology, University of Leuven (KU Leuven), Leuven, Belgium;Department of Neurology, University Hospitals Leuven, Leuven, Belgium;Experimental Neurology (Department of Neurosciences), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, Belgium

关键词: Immunosuppression;    Rapamune;    Sirolimus;    Motor neuron disease;    Amyotrophic lateral sclerosis;    Neurodegeneration;    Rapamycin;    Autophagy;   

Others  :  862185
DOI  :  10.1186/1750-1326-8-31

 received in 2013-04-16, accepted in 2013-09-04,  发布年份 2013

【 摘 要 】

Background

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. Disease pathophysiology is complex and not yet fully understood, but is proposed to include the accumulation of misfolded proteins, as aggregates are present in spinal cords from ALS patients and in ALS model organisms. Increasing autophagy is hypothesized to be protective in ALS as it removes these aggregates. Rapamycin is frequently used to increase autophagy, but is also a potent immune suppressor. To properly assess the role of rapamycin-induced autophagy, the immune suppressive role of rapamycin should be negated.

Findings

Autophagy is increased in the spinal cord of ALS mice. Dietary supplementation of rapamycin increases autophagy, but does not increase the survival of mutant SOD1 mice. To measure the effect of rapamycin in ALS independent of immunosuppression, we tested the effect of rapamycin in ALS mice deficient of mature lymphocytes. Our results show that rapamycin moderately increases the survival of these ALS mice deficient of mature lymphocytes.

Conclusions

Rapamycin could suppress protective immune responses while enhancing protective autophagy reactions during the ALS disease process. While these opposing effects can cancel each other out, the use of immunodeficient mice allows segregation of effects. Our results indicate that maximal therapeutic benefit may be achieved through the use of compounds that enhance autophagy without causing immune suppression.

【 授权许可】

   
2013 Staats et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Logroscino G, Traynor BJ, Hardiman O, Chio A, Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E: Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010, 81:385-390.
• [2]Julien JP, Kriz J: Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta 2006, 1762:1013-1024.
• [3]Ticozzi N, Ratti A, Silani V: Protein aggregation and defective RNA metabolism as mechanisms for motor neuron damage. CNS Neurol Disord Drug Targets 2010, 9:285-296.
• [4]Ido A, Fukuyama H, Urushitani M: Protein misdirection inside and outside motor neurons in amyotrophic lateral sclerosis (ALS): a possible clue for therapeutic strategies. Int J Mol Sci 2011, 12:6980-7003.
• [5]Shen X, Ying H, Qiu Y, Park JS, Shyam R, Chi ZL, Iwata T, Yue BY: Processing of optineurin in neuronal cells. J Biol Chem 2011, 286:3618-3629.
• [6]Miyakawa T, Maeda A, Yamazawa T, Hirose K, Kurosaki T, Iino M: Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes. EMBO J 1999, 18:1303-1308.
• [7]Tian F, Morimoto N, Liu W, Ohta Y, Deguchi K, Miyazaki K, Abe K: In vivo optical imaging of motor neuron autophagy in a mouse model of amyotrophic lateral sclerosis. Autophagy 2011, 7:985-992.
• [8]Morimoto N, Nagai M, Ohta Y, Miyazaki K, Kurata T, Morimoto M, Murakami T, Takehisa Y, Ikeda Y, Kamiya T, Abe K: Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res 2007, 1167:112-117.
• [9]Sasaki S: Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2011, 70:349-359.
• [10]Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E: Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 2009, 29:13578-13588.
• [11]Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC: Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 2010, 133:93-104.
• [12]Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ, Rubinsztein DC: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004, 36:585-595.
• [13]Wang IF, Guo BS, Liu YC, Wu CC, Yang CH, Tsai KJ, Shen CK: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci USA 2012, 109:15024-15029.
• [14]Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 2009, 23:2294-2306.
• [15]Heitman J, Movva NR, Hall MN: Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991, 253:905-909.
• [16]Bhattacharya A, Bokov A, Muller FL, Jernigan AL, Maslin K, Diaz V, Richardson A, Van Remmen H: Dietary restriction but not rapamycin extends disease onset and survival of the H46R/H48Q mouse model of ALS. Neurobiol Aging 2012, 33:1829-1832.
• [17]Thomson AW, Turnquist HR, Raimondi G: Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009, 9:324-337.
• [18]Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC: T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci USA 2008, 105:17913-17918.
• [19]Beers DR, Henkel JS, Zhao W, Wang J, Appel SH: CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci USA 2008, 105:15558-15563.
• [20]Patel BP, Hamadeh MJ: Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis. Clin Nutr 2009, 28:604-617.
• [21]Speakman JR, Mitchell SE: Caloric restriction. Mol Aspects Med 2011, 32:159-221.
• [22]Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE: RAG-1-deficient mice have no mature B and T lymphocytes. Cell 1992, 68:869-877.
• [23]Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH: Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 2011, 134:1293-1314.
• [24]Ching JK, Elizabeth SV, Ju JS, Lusk C, Pittman SK, Weihl CC: mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 2013, 22:1167-1179.
• [25]Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al.: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460:392-395.