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

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Tatenhorst, Lars, Eckermann, Katrin, Dambeck, Vivian, Fonseca-Ornelas, Luis, Walle, Hagen, Lopes da Fonseca, Tomás, Koch, Jan C., Becker, Stefan +5 more·2016·Acta Neuropathologica Communications
DOI 10.1186/s40478-016-0310-yPMC PMC4840958
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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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  • In vivo, ROCK inhibition using Fasudil decreases midbrain α-synuclein pathology and improves motor and cognitive functions in a transgenic mouse model expressing human α-synuclein with the A53T PD mutation.

    “In vivo, ROCK inhibition using Fasudil was shown to decrease midbrain α-synuclein pathology and improve motor and cognitive functions in a transgenic mouse model expressing human α-synuclein with the A53T PD mutation [175].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [175]

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Authors
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.
Affiliations
  • Universitätsmedizin Göttingen (DE)
  • Max Planck Institute for Biophysical Chemistry (DE)
  • German Center for Neurodegenerative Diseases (DE)
Corresponding author
Lingor, Paul
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2016-04-22
Volume
4
Issue
1
Pages
39-39
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-016-0310-y
PMC
PMC4840958
OpenAlex
W2339242828
Cited by
158
References
1
Citations by year
2026: 6 · 2025: 21 · 2024: 23 · 2023: 23 · 2022: 18 · 2021: 16 · 2020: 16 · 2019: 16 · 2018: 12 · 2017: 7
FWCI
7.54
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, other-oa)
  • GRO (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Else Kröner-Fresenius-Stiftung
  • Fundação para a Ciência e a Tecnologia (SFRH/BD/74881/2010)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
fasudil, alpha-synuclein aggregation, Parkinson's disease, A53T alpha-synuclein, transgenic mouse model, disease-modifying therapy, synucleinopathies, motor and cognitive function, drug repurposing
MeSH terms
Amides, Animals, Brain, Carrier Proteins, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Humans, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Parkinson Disease, Psychomotor Performance, Pyridines, Time Factors, Tyrosine 3-Monooxygenase, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Recognition, Psychology, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, alpha-Synuclein, Protein Aggregates

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