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Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease.
Acta Neuropathol Commun. 2016 Apr 22; 4:39.AN

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced α-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of α-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on α-Syn pathology in vivo in a transgenic mouse model overexpressing human α-Syn bearing the A53T mutation (α-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in α-Syn(A53T) mice as determined by Catwalk(TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of α-Syn pathology in the midbrain of α-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with α-Syn and attenuates α-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies.

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Authors+Show Affiliations

Tatenhorst L
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Eckermann K
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Dambeck V
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Fonseca-Ornelas L
Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.
Walle H
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Lopes da Fonseca T
Deparment of NeuroDegeneration and Restorative Research, University Medicine Göttingen, Waldweg 33, 37073, Göttingen, Germany. Instituto de Fisiologia, Faculty of Medicine, University of Lisbon, Lisboa, 1649-028, Portugal.
Koch JC
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany.
Becker S
Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.
Tönges L
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. Current address: Neurological Clinic, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.
Bähr M
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany.
Outeiro TF
Deparment of NeuroDegeneration and Restorative Research, University Medicine Göttingen, Waldweg 33, 37073, Göttingen, Germany. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany.
Zweckstetter M
Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany. German Center for Neurodegenerative Diseases (DZNE), Am Fassberg 11, 37077, Göttingen, Germany.
Lingor P
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. plingor@gwdg.de. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany. plingor@gwdg.de.

MeSH

1-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAmidesAnimalsBrainCarrier ProteinsCell Line, TumorDisease Models, AnimalEnzyme InhibitorsGene Expression RegulationHumansMiceMice, TransgenicMutationNerve Tissue ProteinsParkinson DiseaseProtein AggregatesProtein Kinase InhibitorsPsychomotor PerformancePyridinesRecognition, PsychologyTime FactorsTyrosine 3-Monooxygenasealpha-Synuclein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27101974

Citation

Tatenhorst, Lars, et al. "Fasudil Attenuates Aggregation of Α-synuclein in Models of Parkinson's Disease." Acta Neuropathologica Communications, vol. 4, 2016, p. 39.
Tatenhorst L, Eckermann K, Dambeck V, et al. Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. Acta Neuropathol Commun. 2016;4:39.
Tatenhorst, L., Eckermann, K., Dambeck, V., Fonseca-Ornelas, L., Walle, H., Lopes da Fonseca, T., Koch, J. C., Becker, S., Tönges, L., Bähr, M., Outeiro, T. F., Zweckstetter, M., & Lingor, P. (2016). Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. Acta Neuropathologica Communications, 4, 39. https://doi.org/10.1186/s40478-016-0310-y
Tatenhorst L, et al. Fasudil Attenuates Aggregation of Α-synuclein in Models of Parkinson's Disease. Acta Neuropathol Commun. 2016 Apr 22;4:39. PubMed PMID: 27101974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. AU - Tatenhorst,Lars, AU - Eckermann,Katrin, AU - Dambeck,Vivian, AU - Fonseca-Ornelas,Luis, AU - Walle,Hagen, AU - Lopes da Fonseca,Tomás, AU - Koch,Jan C, AU - Becker,Stefan, AU - Tönges,Lars, AU - Bähr,Mathias, AU - Outeiro,Tiago F, AU - Zweckstetter,Markus, AU - Lingor,Paul, Y1 - 2016/04/22/ PY - 2016/04/09/received PY - 2016/04/09/accepted PY - 2016/4/23/entrez PY - 2016/4/23/pubmed PY - 2016/10/16/medline KW - A53T mouse model KW - Fasudil KW - Parkinson’s disease KW - α-synuclein aggregation SP - 39 EP - 39 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 4 N2 - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced α-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of α-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on α-Syn pathology in vivo in a transgenic mouse model overexpressing human α-Syn bearing the A53T mutation (α-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in α-Syn(A53T) mice as determined by Catwalk(TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of α-Syn pathology in the midbrain of α-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with α-Syn and attenuates α-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/27101974/Fasudil_attenuates_aggregation_of_α_synuclein_in_models_of_Parkinson's_disease_ DB - PRIME DP - Unbound Medicine ER -