Inhibition of HDAC6 activity protects dopaminergic neurons from alpha-synuclein toxicity

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.www.nature.com/scientificreports www.nature.com/scientificreports/ induced by human alpha-synuclein overexpression in the substantia nigra pars compacta 15 . We already used this rat model to test the effect of other putative therapeutic targets, such as sirtuin 2 (SIRT2) 8 . We adapted the experimental design in order to phenocopy early-onset PD defects. To specifically inhibit HDAC6, we used Tubastatin A and tested it as a preventive drug in this early onset model of PD. We found that inhibition of HDAC6 activity by Tubastatin A has a disease modifier effect in the substantia nigra pars compacta by protecting dopaminergic neurons against alpha-synuclein toxicity, accompanied by reduced astrogliosis. Our results demonstrate that Tubastatin A treatment lead to differential protein expression compared to the vehicle. Interestingly, we found that Hsc70 and Lamp2 proteins were upregulated by Tubastatin A, whereas alpha-synuclein was downregulated. Importantly, we did not detect phosphorylation of alpha-synuclein at serine position 129, an accepted marker of pathological alpha-synuclein, in the rats treated with Tubastatin A. Overall, our work supports the hypothesis that specific inhibition of HDAC6 activity increases alpha-synuclein acetylation, up-regulates key members of the chaperone-mediated autophagy, and reduces alpha-synuclein expression and toxicity. Therefore, HDAC6 is a potential therapeutic target for PD and other alpha-synucleinopathies. Scientific RepoRtS |(2020) 10:6064 | https://doi.CM3050S) at a 30 µm thickness. Sections were collected as serial coronal free-floating sections in a storage solution (0.1 M PBS; 0.1% sodium azide), stored at 4 °C until use.Scientific RepoRtS | (2020) 10:6064 | https://doi.

Acetylation of NDUFV1 induced by a newly synthesized HDAC6 inhibitor HGC rescues dopaminergic neuron loss in Parkinson models

“…All these findings suggest that HDAC6, together with NDUFV1, might be drug targets for developing agents to attenuate neurodegeneration in PD or potentially other neurodegenerative disorders with mitochondrial dysfunction. Most recently, one study has shown that inhibition of HDAC6 activity protects dopaminergic neurons from α-synuclein toxicity in rats ( Francelle et al., 2020 ), which further supports our conclusions.…”

Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma

“…In support of this, co-culture of human pluripotent stem cell (iPSC)-derived astrocytes and neurons from control and PD patients, showed that chemical enhancement of CMA protected both from degeneration (di Domenico et al, 2019 ). In line with this, the treatment with the selective inhibitor of HDAC6 Tubastatin A reduces both astrocyte reactivity and neuron degeneration induced by α-synuclein in a rat PD model, increasing Lamp2a and Hsc70 expression and partially inducing α-synuclein acetylation (Francelle et al, 2020 ). Crosstalk between different protein degradation systems is also noteworthy in PD pathogenesis.…”

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

“…Modulators of α‐synuclein acetylation, 4‐hydroxy‐2‐neonal oxidation, O‐GlcNAcylation and phosphorylation might be candidate agents to preclude PD‐related synucleinopathy. Other options are (i) repurposing of drugs used for the treatment of other diseases, 269 (ii) novel DA agonists such as PF‐06649751, a noncatechol‐based D1/D5 DA receptor partial agonist, 270 (iii) neurotransmitter enhancers (e.g., IRL752, a small‐molecule compound with regioselective effects on NA, DA, and acetylcholine neurotransmission in the cerebral cortex, 271 (iv) chemical chaperones to block the misfolding and aggregation of α‐synuclein, 272 (v) epigenetic drugs 67,273 and miRNA‐based therapeutics, 274 and (vi) alternative interventions with still undefined consequences, such as neuronal cell replacement therapy, autologous pluripotent stem cells (iPSCs) 262,275 or gene therapy 276–278 …”