Homocysteine induces glyceraldehyde-3-phosphate dehydrogenase acetylation and apoptosis in the neuroblastoma cell line Neuro2a

Abstract

High plasma levels of homocysteine (Hcy) promote the progression of neurodegenerative diseases. However, the mechanism by which Hcy mediates neurotoxicity has not been elucidated. We observed that upon incubation with Hcy, the viability of a neuroblastoma cell line Neuro2a declined in a dose-dependent manner, and apoptosis was induced within 48 h. The median effective concentration (EC50) of Hcy was approximately 5 mM. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nuclear translocation and acylation has been implicated in the regulation of apoptosis. We found that nuclear translocation and acetylation of GAPDH increased in the presence of 5 mM Hcy and that higher levels of acetyltransferase p300/CBP were detected in Neuro2a cells. These findings implicate the involvement of GAPDH in the mechanism whereby Hcy induces apoptosis in neurons. This study highlights a potentially important pathway in neurodegenerative disorders, and a novel target pathway for neuroprotective therapy.

Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism

“…In Drosophila melanogaster , EtOH and benzyl alcohol induce mutual cross‐tolerance, indicating that they share a common mechanism for producing tolerance. EtOH, its major metabolite acetate, and HHcy have been shown to induce histone H3 acetylation (Fang et al., ; Shukla et al., ). EtOH enhanced histone H3K9 acetylation in a dose‐ and time‐dependent manner in primary cultures of hepatocytes, without affecting H3K14 acetylation, demonstrating the specificity of EtOH in regulating covalent modifications to histone proteins.…”

Quantitative Acetylomics Revealed Acetylation-Mediated Molecular Pathway Network Changes in Human Nonfunctional Pituitary Neuroendocrine Tumors

“…It acidified extracellular matrix (ECM), and subsequently activated matrix metalloproteinase and cathepsin to increase ECM degradation, which paved the way for many basic cell behaviors, including cell migration (76). Some overlapped molecules, such as HSPA8 and GAPDH, were found to be regulated by acetylation and deacetylation and associated with invasiveness of cancers (77)(78)(79)(80)(81). The interesting mechanisms that how protein acetylation affects NF-PitNETs metabolic reprogram to enhance its invasiveness are worthy further investigating, which is promised to provide a novel therapeutic target for NF-PitNET radical treatment.…”

Glyceraldehyde-3-phosphate Dehydrogenase Is a Multifaceted Therapeutic Target

“…On the other hand, GAPDH may form a direct complex with p53, leading to the activation of AMPA receptor and significantly increasing both the expression of p53 and its phosphorylation at Ser46 [53]; this modification is meaningful because it was found to activate apoptosis [54]. Importantly, according to several reports intranuclear translocation of GAPDH correlates with p53 activation and transcription of BAX, PUMA and p21, leading to p53-dependent cell death [55,56]. Despite these convincing reports, a pathway of apoptosis that is predominantly affected by SNO-GAPDH-Siah1 nuclear translocation needs further elucidation.…”