Downregulation of eEF1A/EFT3-4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein protein and selective death of dopaminergic (DA) neurons in the substantia nigra of the midbrain. Although the molecular pathogenesis of PD is not completely understood, a recent study has reported that eukaryotic translation elongation factor 1 alpha (eEF1A) declined in the PD-affected brain. Therefore, the roles of eEF1A1 and eEF1A2 in the prevention of DA neuronal cell death in PD are aimed to be investigated. Herein, by using Caenorhabditis elegans as a PD model, we investigated the role of eft-3/eft-4, the worm homolog of eEF1A1/eEF1A2, on 6-hydroxydopamine (6-OHDA)-induced DA neuron degeneration. Our results demonstrated that the expressions of eft-3 and eft-4 were decreased in the 6-OHDA-induced worms. RNA interference (RNAi) of eft-3 and eft-4 resulted in dramatic exacerbation of DA neurodegeneration induced by 6-OHDA, as well as aggravated the food-sensing behavior, ethanol avoidance, and decreased lifespan when compared with only 6-OHDA-induced worms. Moreover, downregulation of eft-3/4 in 6-OHDA-induced worms suppressed the expression of the anti-apoptotic genes, including PI3K/age-1, PDK-1/pdk-1, mTOR/let-363, and AKT-1,2/akt-1,2, promoting the expression of apoptotic genes such as BH3/egl-1 and Caspase-9/ced-3. Collectively, these findings indicate that eEF1A plays an important role in the 6-OHDA-induced neurodegeneration through the phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (Akt)/mammalian target of rapamycin (mTOR) pathway and that eEF1A isoforms may be a novel and effective pro-survival factor in protective DA neurons against toxin-induced neuronal death.

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

“…In the transgenic BZ555 worms, the morphological pattern of dopamine neurons could be observed through the dopamine transporter protein DAT-1::GFP. Selective degeneration of dopamine neurons in C. elegans can be induced by 6-hydroxydopamine (6-OHDA) [ 67 ]. Our results showed that 6-OHDA decreased the average fluorescence intensity of dopamine neurons in the BZ555 worms from 48.418 to 20.168, while HBA treatment remained the average fluorescence intensity at 30.151 (Figures 2(c) and 2(d) ), suggesting that HBA treatment protected the degeneration of head neurons in BZ555 worms.…”

METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury

“…Expressions of Bax and cleaved caspase 3 were increased while Bcl-2 expression was decreased in OGD-treated neurons after EEF1A2 overexpression and Perifosine treatment. EFF1A is pivotal in 6-OHDA-induced neurodegeneration via the PI3K/Akt/mTOR pathway [ 46 ]. Fangji decoction represses hippocampal neuron apoptosis by regulating the Akt/mTOR pathway in febrile seizures [ 47 ].…”

Neurorescue Effects of Frondoside A and Ginsenoside Rg3 in C. elegans Model of Parkinson’s Disease

“…The RNA samples were stored at −80 °C until use. The RNA concentration was quantified using NanoDrop 2000 Spectrophotometer (Thermo Scientific, Waltham, MA, USA) [ 61 ]. For quantitative gene expression analyses, high capacity complementary DNA (cDNA) was generated from 2 µg of RNA, using the iScriptTMReverse Transcription Supermix for RT–qPCR (Bio-Rad, Hercules, CA, USA).…”