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

It has been shown that histone deacetylase (HDAC) inhibitors hold considerable therapeutic potentials for treating neurodegeneration-related diseases including Parkinson disease (PD). Here, we synthesized an HDAC inhibitor named as HGC and examined its neuroprotective roles in PD models. Our results showed that HGC protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced insults. Furthermore, in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model mice, HGC application rectifies behavioral defects, improves tyrosine hydroxylase-positive neurons in the midbrain, and maintains mitochondrial integrity and functions. Mechanistically, mass spectrometry data revealed that HGC stimulates acetylation modification at lysine 28 of NDUFV1. Inhibition of HDAC6 by HGC is responsible for this acetylation modification. Functional tests showed that, as well as HGC, NDUFV1 exhibits beneficial roles against MPP+ injuries. Moreover, knockdown of NDUFV1 abolishes the neuroprotective roles of HGC. Taken together, our data indicate that HGC has a great therapeutic potential for treating PD and NDUFV1 might be a target for developing drugs against PD.