Objective: To explore the effects of selective inhibition of HDAC4, on levels of α-syn and autophagy-related proteins in PD. To discuss the mechanism for the neuroprotective effects of HDAC inhibitors, to find a way to regulate autophagy and reduce neurotoxicity of α-syn moderately, and to give a new clue to the targeted therapy in PD.

Background: Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, and its predominant pathologies is the pathogenic aggregation of α-synuclein (α-syn) in vulnerable neurons. One of the degradation pathways of α-syn is the autophagy/lysosomal pathway, which is partially regulated by the acetylation of histones. Meanwhile, HDACs also affect the activation of autophagy. Multiple HDAC inhibitors have been proved to have neuroprotective effects in PD models. However, the HDAC inhibitors used in most present studies have broad spectrums and block multiple HDACs in a time. Thus it is difficult to figure out the specific mechanism implicated in their neuroprotective effects, as well as their complicated side effects and neurotoxicity.

Methods: Mc1568 was used to inhibit HDAC4 in rotenone-treated SH-SY5Y cells; then expression levels of α-syn were analyzed by Western blot, and cell viability was analyzed by Cell Counting Kit-8 (CCK-8). HDAC4 was knocked-down or overexpressed in SY5Y cells by shRNA or inserted HDAC4 sequence; after treatment with rotenone, expression levels of α-syn and autophagy-related proteins (such as LC3, Beclin-1 and p62) were analyzed by Western blot.

Results: Rotenone induced a significant increase in α-syn levels in SH-SY5Y cells. Mc1568 reduced α-syn in rotenone model in a dose-dependent manner. The overexpression of HDAC4 repressed the expression of autophagy-related proteins including LC3-Ⅱ and Beclin-1 in rotenone-treated SH-SY5Y cells, while the knockdown(KD) of HDAC4 upregulated the expression of autophagy-related proteins, and significantly abolished the abnormal increase in α-syn levels induced by rotenone.

Conclusions: The selective inhibition of HDAC4 had neuroprotective effects in cellular model of PD. HDAC4 repressed the autophagy pathway, and promoted the accumulation of α-syn in rotenone-induced cellular model of PD. However, Mc1568 reversed the abnormal increase in α-syn levels. Knockdown of HDAC4 expression also promoted the degradation of α-syn by activation of autophagy, and therefore abolished the rotenone-induced neurotoxicity.

References: [1] Harrison, I.F. and D.T. Dexter, Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson’s disease? Pharmacology & Therapeutics, 2013. 140(1): p. 34-52.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibition-of-hdac4-attenuates-rotenone-induced-abnormal-increase-of-%ce%b1-synuclein-levels-and-affects-autophagic-flux-in-human-dopaminergic-sh-sy5y-cells/