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Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease

Lookup NU author(s): Professor Tiago Outeiro

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tonges L, Bahr M, Outeiro TF, Zweckstetter M, Lingor P

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica Communications

Year: 2016

Volume: 4

Online publication date: 22/04/2016

Acceptance date: 09/04/2016

Date deposited: 20/12/2017

ISSN (electronic): 2051-5960

Publisher: BioMed Central Ltd

URL: https://doi.org/10.1186/s40478-016-0310-y

DOI: 10.1186/s40478-016-0310-y

PubMed id: 27101974


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