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microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease.
J Neurosci. 2016 Feb 24; 36(8):2383-90.JN

Abstract

Increasing evidence points to inflammation as a chief mediator of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein α-synuclein (α-syn). Recently, microRNAs, small, noncoding RNAs involved in regulating gene expression at the posttranscriptional level, have been recognized as important regulators of the inflammatory environment. Using an array approach, we found significant upregulation of microRNA-155 (miR-155) in an in vivo model of PD produced by adeno-associated-virus-mediated expression of α-syn. Using a mouse with a complete deletion of miR-155, we found that loss of miR-155 reduced proinflammatory responses to α-syn and blocked α-syn-induced neurodegeneration. In primary microglia from miR-155(-/-) mice, we observed a markedly reduced inflammatory response to α-syn fibrils, with attenuation of major histocompatibility complex class II (MHCII) and proinflammatory inducible nitric oxide synthase expression. Treatment of these microglia with a synthetic mimic of miR-155 restored the inflammatory response to α-syn fibrils. Our results suggest that miR-155 has a central role in the inflammatory response to α-syn in the brain and in α-syn-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to α-syn. These data implicate miR-155 as a potential therapeutic target for regulating the inflammatory response in PD.

Authors+Show Affiliations

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294 dstandaert@uab.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26911687

Citation

Thome, Aaron D., et al. "MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 8, 2016, pp. 2383-90.
Thome AD, Harms AS, Volpicelli-Daley LA, et al. MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J Neurosci. 2016;36(8):2383-90.
Thome, A. D., Harms, A. S., Volpicelli-Daley, L. A., & Standaert, D. G. (2016). MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(8), 2383-90. https://doi.org/10.1523/JNEUROSCI.3900-15.2016
Thome AD, et al. MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J Neurosci. 2016 Feb 24;36(8):2383-90. PubMed PMID: 26911687.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. AU - Thome,Aaron D, AU - Harms,Ashley S, AU - Volpicelli-Daley,Laura A, AU - Standaert,David G, PY - 2016/2/26/entrez PY - 2016/2/26/pubmed PY - 2016/7/1/medline KW - Parkinson disease KW - microRNA-155 KW - microglia KW - neurodegeneration KW - neuroinflammation KW - α-synuclein SP - 2383 EP - 90 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 36 IS - 8 N2 - Increasing evidence points to inflammation as a chief mediator of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein α-synuclein (α-syn). Recently, microRNAs, small, noncoding RNAs involved in regulating gene expression at the posttranscriptional level, have been recognized as important regulators of the inflammatory environment. Using an array approach, we found significant upregulation of microRNA-155 (miR-155) in an in vivo model of PD produced by adeno-associated-virus-mediated expression of α-syn. Using a mouse with a complete deletion of miR-155, we found that loss of miR-155 reduced proinflammatory responses to α-syn and blocked α-syn-induced neurodegeneration. In primary microglia from miR-155(-/-) mice, we observed a markedly reduced inflammatory response to α-syn fibrils, with attenuation of major histocompatibility complex class II (MHCII) and proinflammatory inducible nitric oxide synthase expression. Treatment of these microglia with a synthetic mimic of miR-155 restored the inflammatory response to α-syn fibrils. Our results suggest that miR-155 has a central role in the inflammatory response to α-syn in the brain and in α-syn-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to α-syn. These data implicate miR-155 as a potential therapeutic target for regulating the inflammatory response in PD. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/26911687/microRNA_155_Regulates_Alpha_Synuclein_Induced_Inflammatory_Responses_in_Models_of_Parkinson_Disease_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=26911687 DB - PRIME DP - Unbound Medicine ER -