Abstract
The neuropathological hallmarks of Parkinson’s disease include preferential vulnerability of dopaminergic neurons of the substantia nigra pars compacta, and accumulation of intraneuronal protein inclusions known as Lewy bodies. These inclusions contain, among other proteins, aggregated alpha-synuclein and histone deacetylase 6 (HDAC6). In our study we found that selective inhibition of HDAC6 activity by Tubastatin A has protective effects in a rat model of Parkinson’s disease. We provide evidence that this protection may be due to the activation of chaperone-mediated autophagy through the up-regulation of key members of this pathway. Moreover, Tubastatin A significantly inhibited the expression of a toxic form of alpha-synuclein that is phosphorylated at serine position 129. Tubastatin A treatment also permitted to partially modulate neuroinflammation. Taken together, our study highlights the neuroprotective effects of Tubastatin A in a rat model of Parkinson’s disease and provides mechanistic insight in Tubastatin A-mediated protection against alpha-synuclein toxicity and substantia nigra degeneration. These findings are of potential therapeutic value in Parkinson’s disease and other synucleinopathies.
| Original language | English (US) |
|---|---|
| Article number | 6064 |
| Journal | Scientific reports |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2020 |
Funding
L.F. was funded by the Alexander-von-Humboldt Foundation with a Postdoctoral Researcher Fellowship. This work was supported by the Alexander-von-Humboldt Foundation, the Medical Faculty of the University of Heidelberg and the German Research Council funded Center for Nanoscale Microscopy and Physiology of the Brain (CNMPB). We gratefully acknowledge Sebastian Kügler who provided the viral vector expressing alpha-synuclein and contributed to the in vivo experimental design and setup. We thank him, Rolf Sprengel, Margit Burmeister, Olaf Riess and Beate Niesler for their comments on the manuscript. We thank Dr. Christian Ackermann at the Nikon Imaging Center, University of Heidelberg, Germany, for technical assistance, and Dr. Thomas Ruppert and Sabine Merker at the ZMBH Mass Spectrometry Core facility, University of Heidelberg, Germany, for precious support.
ASJC Scopus subject areas
- General