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

Abstract

Summary 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.

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

“…219 The brain is a very sensitive part of body, so remains highly vulnerable to pathogens and damage causing neurodegenerative disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, brain tumors, and Alzheimer's disease. 220,221 These illnesses are main cause of neuronal death, including neural strokes, which are a result of different complications like calciumhomeostasis loss, cytotoxicity, metabolic failure, and oxidative stress. 222 Many pyridine-or dihydropyridine-containing drugs are being evaluated for the treatment of neurodegenerative disorders 223 (Figure 42).…”

Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice

“…To analyze electron chain transports (ETC) complex I activity, mitochondria were isolated from kidneys by using a kit (MITOISO2; Sigma‐Aldrich). ETC complex I activity was assayed with a mitochondrial complex I activity assay kit (MAK359; Sigma‐Aldrich) using a previous described method (B. Li et al, 2021). Briefly, 1–5 μg of mitochondrial samples were incubated with 57 μl of complex I assay buffer, 2 μl of decylubiquinone and 9 μl of complex I dye.…”

“…Briefly, 12 h‐post UUO surgery, 10 μg of the plasmid expressing Ndufv1 was given to mice by tail vein injection in 8–12 s. For Mock group, mice were received 10 μg of the empty vector pcDNA3.1 (+). The plasmid expressing Ndufv1 was described elsewhere (B. Li et al, 2021). After anaesthetization, mice were sacrificed and the obstructed kidneys were collected for further analyses including gene expression and fibrosis evaluation.…”

Resveratrol ameliorates muscle atrophy in chronic kidney disease via the axis of SIRT1/FoxO1

“…Immunohistochemical analysis was performed by using the method describe previously (B. Li et al, 2021). In brief, after dewaxing, paraffin sections of rat tibialis anterior were subjected to routine antigen repair and blocked with protein blocking solution for 1 h. The primary antibody (mouse monoclonal anti-Dystrophin antibody, 1:300; Abcam, ab7164) was dropwise added and incubated with the slices at 4 C overnight, and the secondary antibody was incubated at 37 C for 30 min.…”