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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.
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1 Ruprecht-Karls-University Heidelberg, Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373); University Medical Center Goettingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Goettingen, Germany (GRID:grid.411984.1) (ISNI:0000 0001 0482 5331)
2 University Medical Center Goettingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Goettingen, Germany (GRID:grid.411984.1) (ISNI:0000 0001 0482 5331); Max Planck Institute for Experimental Medicine, Goettingen, Germany (GRID:grid.419522.9) (ISNI:0000 0001 0668 6902)
3 Ruprecht-Karls-University Heidelberg, Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373)