English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
 
 
DownloadE-Mail
  Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson's disease.

Tatenhorst, L., Eckermann, K., Dambeck, V., Fonseca-Ornelas, L., Walle, H., da Fonseca, T. L., et al. (2016). Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson's disease. Acta Neuropathologica Communications, 4: 39. doi:10.1186/s40478-016-0310-y.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-C4C9-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-25C0-D
Genre: Journal Article

Files

show Files
hide Files
:
2301192.pdf (Publisher version), 2MB
Name:
2301192.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-

Locators

show

Creators

show
hide
 Creators:
Tatenhorst, L., Author
Eckermann, K., Author
Dambeck, V., Author
Fonseca-Ornelas, L., Author
Walle, H., Author
da Fonseca, T. L., Author
Koch, J. C., Author
Becker, S.1, Author              
Toenges, L., Author
Bahr, M., Author
Outeiro, T. F., Author
Zweckstetter, M.2, Author              
Lingor, P., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

Content

show
hide
Free keywords: alpha-synuclein aggregation; Fasudil; Parkinson's disease; A53T mouse model
 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 (alpha-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 alpha-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 alpha-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 alpha-Syn pathology in vivo in a transgenic mouse model overexpressing human alpha-Syn bearing the A53T mutation (alpha-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in alpha-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 alpha-Syn pathology in the midbrain of alpha-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with alpha-Syn and attenuates alpha-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies.

Details

show
hide
Language(s): eng - English
 Dates: 2016-04-22
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1186/s40478-016-0310-y
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Acta Neuropathologica Communications
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: 17 Volume / Issue: 4 Sequence Number: 39 Start / End Page: - Identifier: -