Superoxide dismutase-1 (SOD1) and ataxin-3 are two neurodegenerative disease proteins in association with familial amyotrophic lateral sclerosis and Machado–Joseph disease/spinocerebellar ataxia type 3. Both normal and mutant types of SOD1 and ataxin-3 are degraded by the proteasome. It was recently reported that these two proteins are associated with the endoplasmic reticulum (ER). Mammalian gp78 is an E3 ubiquitin ligase involved in ER-associated degradation (ERAD). Here, we show that gp78 interacts with both SOD1 and ataxin-3. Overexpression of gp78 promotes the ubiquitination and degradation of these two proteins, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 and ataxin-3 to target them for ERAD.

Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.

A growing number of studies have indicated that extracellular vesicles (EVs), such as exosomes, are involved in the development of neurodegenerative diseases. Components of EVs with biological effects like proteins, nucleic acids, or other molecules can be delivered to recipient cells to mediate physio-/pathological processes. For instance, some aggregate-prone proteins, such as β-amyloid and α-synuclein, had been found to propagate through exosomes. Therefore, either an increase of detrimental molecules or a decrease of beneficial molecules enwrapped in EVs may fully or partly indicate disease progression. Numerous studies have demonstrated that dysbiosis of the gut microbiota and neurodegeneration are tightly correlated, well-known as the “gut–brain axis”. Accumulating evidence has revealed that the gut bacteria-derived EVs play a pivotal role in mediating microbe–host interactions and affect the function of the “gut–brain axis”, which subsequently contributes to the pathogenesis of neurodegenerative diseases. In this review, we first briefly discuss the role of EVs from mammalian cells and microbes in mediating the progression of neurodegenerative diseases, and then propose a novel strategy that employs EVs of plants (plant cell-derived exosome-like nanoparticles) for treating neurodegeneration.

Introduction: Emerging evidence implicates gut microbiota dysbiosis as a key modulator for the pathogenesis of Alzheimer’s disease (AD) via the gut-brain axis. To investigate the causal role of microbial communities in AD progression, we performed fecal microbiota transplantation (FMT) in APP/PS1 transgenic mice using donor microbiota from healthy wild-type mice or dextran sulfate sodium (DSS)-induced colitis mice. Methods: Cognitive function, amyloid-beta (Aβ) pathology, and pro-inflammatory cytokine levels were assessed in mice. 16S ribosomal RNA sequencing of gut microbiota and bioinformatic functional analyses were applied to identify the specific microbial communities potentially involved in AD progression. Results: FMT-WT mice (fecal microbiota transplantation from healthy wild-type mice) exhibited significant improvements in spatial memory (Morris Water Maze), exploratory behavior (Y-maze), and locomotor activity (Open Field Test), alongside reduced Aβ plaque burden and normalized expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in both gut and brain tissues. Conversely, FMT-DSS mice (fecal microbiota transplantation from DSS-treated donors) displayed exacerbated cognitive deficits, heightened Aβ deposition, and elevated pro-inflammatory cytokine levels. Microbial profiling revealed stark contrasts: FMT-WT mice harbored beneficial taxa (Bacteroides, Lachnospiraceae) linked to anti-inflammatory products like short-chain fatty acid, while FMT-DSS mice showed blooms of pathogenic genera (Erysipelatoclostridium, Enterobacteriaceae) associated with neurotoxic metabolites. Functional analyses predicted enrichment of neuroprotective pathways (e.g., lysine metabolism) in FMT-WT and pro-inflammatory pathways (e.g., carbon metabolism) in FMT-DSS. Crucially, neuroinflammation occurred independently of gut barrier disruption, implicating circulating microbial metabolites as key mediators. Discussion: Our findings demonstrate that gut microbiota composition bidirectionally influences AD progression, with FMT from healthy donors attenuating neuroinflammation and pathology, while colitis-associated dysbiosis exacerbates disease hallmarks. Our study positions microbiota-targeted therapies as a promising strategy to modulate AD progression through the gut-brain axis.

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in various biological processes, including apoptosis, by regulating gene expression. This study was designed to test the hypothesis that ethanol-induced downregulation of miR-135a contributes to ethanol-induced apoptosis in neural crest cells (NCCs) by upregulating Siah1 and activating the p38 mitogen-activated protein kinase (MAPK)/p53 pathway. We found that treatment with ethanol resulted in a significant decrease in miR-135a expression in both NCCs and zebrafish embryos. Ethanol-induced downregulation of miR-135a resulted in the upregulation of Siah1 and the activation of the p38 MAPK/p53 pathway and increased apoptosis in NCCs and zebrafish embryos. Ethanol exposure also resulted in growth retardation and developmental defects that are characteristic of fetal alcohol spectrum disorders (FASD) in zebrafish. Overexpression of miRNA-135a significantly reduced ethanol-induced upregulation of Siah1 and the activation of the p38 MAPK/p53 pathway and decreased ethanol-induced apoptosis in NCCs and zebrafish embryos. In addition, ethanol-induced growth retardation and craniofacial defects in zebrafish larvae were dramatically diminished by the microinjection of miRNA-135a mimics. These results demonstrated that ethanol-induced downregulation of miR-135a contributes to ethanol-induced apoptosis in NCCs by upregulating Siah1 and activating the p38 MAPK/p53 pathway and that the overexpression of miRNA-135a can protect against ethanol-induced apoptosis in NCCs and craniofacial defects in a zebrafish model of FASD.