ABSTRACT
In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Nucleobindins , tau Proteins , Animals , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Nucleobindins/metabolism , Nucleobindins/genetics , tau Proteins/metabolism , tau Proteins/genetics , Humans , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/metabolism , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Calcium-Binding Proteins/genetics , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Animals, Genetically Modified , Drosophila , Locomotion , LongevityABSTRACT
Dorsal switch protein 1(DSP1), a mammalian homolog of HMGB1, is firstly identified as a dorsal co-repressor in 1994. DSP1 contains HMG-box domain and functions as a transcriptional regulator in Drosophila melanogaster. It plays a crucial role in embryonic development, particularly in dorsal-ventral patterning during early embryogenesis, through the regulation of gene expression. Moreover, DSP1 is implicated in various cellular processes, including cell fate determination and tissue differentiation, which are essential for embryonic development. While the function of DSP1 in embryonic development has been relatively well-studied, its role in the adult Drosophila brain remains less understood. In this study, we investigated the role of DSP1 in the brain by using neuronal-specific DSP1 overexpression flies. We observed that climbing ability and life span are decreased in DSP1-overexpressed flies. Furthermore, these flies demonstrated neuromuscular junction (NMJ) defect, reduced eye size and a decrease in tyrosine hydroxylase (TH)-positive neurons, indicating neuronal toxicity induced by DSP1 overexpression. Our data suggest that DSP1 overexpression leads to neuronal dysfunction and toxicity, positioning DSP1 as a potential therapeutic target for neurodegenerative diseases.
Subject(s)
Drosophila Proteins , Drosophila melanogaster , Nerve Degeneration , Neuromuscular Junction , Neurons , Phenotype , Animals , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Eye/pathology , Longevity/genetics , Nerve Degeneration/pathology , Nerve Degeneration/genetics , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Neurons/metabolism , Neurons/pathology , Transcription Factors/metabolism , Transcription Factors/genetics , Tyrosine 3-Monooxygenase/metabolism , Tyrosine 3-Monooxygenase/geneticsABSTRACT
AIM: We examined the novel role of NUCB1(Nucleobindin-1) associated with longevity in Drosophila melanogaster. METHODS: We measured the lifespan, metabolic phenotypes, and mRNA levels of Drosophila insulin-like peptides (Dilps), the protein level of phosphorylated AKT, and the localization of FOXO and its target gene expressions in the NUCB1 knockdown condition. RESULTS: NUCB1 knockdown flies show an extended lifespan and metabolic phenotypes such as increased circulating glucose level and starvation resistance. The mRNA expression levels of Dilps and the protein level of phosphorylated AKT, a downstream component of insulin signaling, were decreased in NUCB1 knockdown flies compared with the control flies. Also, the nuclear localization of FOXO and its target gene expressions, such as d4E-BP and InR, were elevated. CONCLUSIONS: The results show that NUCB1 knockdown flies exhibits an extended lifespan. These findings suggest that NUCB1 modulates longevity through insulin signaling in Drosophila. Geriatr Gerontol Int 2024; 24: 486-492.