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

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.

• Authors: Lars Tatenhorst, Katrin Eckermann, Vivian Dambeck, Luis Fonseca-Ornelas, Hagen Walle, Tomás Lopes da Fonseca, Jan C Koch, Stefan Becker, Lars Tönges, Mathias Bähr, Tiago F Outeiro, Markus Zweckstetter, Paul Lingor
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 4 Pg. 39 (Apr 22 2016) ISSN: 2051-5960 [Electronic] England
• PMID: 27101974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Carrier Proteins
• Enzyme Inhibitors
• Nerve Tissue Proteins
• Protein Aggregates
• Protein Kinase Inhibitors
• Pyridines
• SNCAIP protein, human
• alpha-Synuclein
• Y 27632
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Tyrosine 3-Monooxygenase
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology, therapeutic use)
• Amides (pharmacology, therapeutic use)
• Animals
• Brain (drug effects, metabolism, pathology)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Mice
• Mice, Transgenic
• Mutation (genetics)
• Nerve Tissue Proteins (metabolism)
• Parkinson Disease (drug therapy, genetics, metabolism)
• Protein Aggregates (drug effects, genetics)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Psychomotor Performance (drug effects)
• Pyridines (pharmacology, therapeutic use)
• Recognition, Psychology (drug effects)
• Time Factors
• Tyrosine 3-Monooxygenase (metabolism)
• alpha-Synuclein (genetics, metabolism)