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Acta Neuropathol Commun. 2016 Apr 22;4:39. doi: 10.1186/s40478-016-0310-y.

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

Author information

1
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
2
Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.
3
Deparment of NeuroDegeneration and Restorative Research, University Medicine Göttingen, Waldweg 33, 37073, Göttingen, Germany.
4
Instituto de Fisiologia, Faculty of Medicine, University of Lisbon, Lisboa, 1649-028, Portugal.
5
DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany.
6
Current address: Neurological Clinic, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.
7
German Center for Neurodegenerative Diseases (DZNE), Am Fassberg 11, 37077, Göttingen, Germany.
8
Deparment of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. plingor@gwdg.de.
9
DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtalle 23, 37073, Göttingen, Germany. plingor@gwdg.de.

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.

KEYWORDS:

A53T mouse model; Fasudil; Parkinson’s disease; α-synuclein aggregation

PMID:
27101974
PMCID:
PMC4840958
DOI:
10.1186/s40478-016-0310-y
[Indexed for MEDLINE]
Free PMC Article

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