ATP6V1E1
V-type proton ATPase subunit E 1 (V-ATPase subunit E 1) (V-ATPase 31 kDa subunit) (p31) (Vacuolar proton pump subunit E 1) [ATP6E] [ATP6E2]
Publications[править]
Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, [[NRXN3]], the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, [[NRXN3]] plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. Our results indicate that the low expression of aging-related [[NRXN3]] may increase AD risk, though the potential mechanism requires further clarification.
MeSH Terms
- Adult
- Aged
- Aging
- Alzheimer Disease
- Down-Regulation
- Gene Expression
- Humans
- Middle Aged
- Nerve Tissue Proteins
- Polymorphism, Single Nucleotide
- Risk Factors
- Young Adult
Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V and V domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.
MeSH Terms
- Adenosine Triphosphatases
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Cell Nucleus
- Drug Delivery Systems
- Enzyme Activation
- Flow Cytometry
- Humans
- Hydrogen-Ion Concentration
- Lysosomes
- Mice
- Mitochondria
- Morpholines
- Phosphorylation
- Protein Kinase Inhibitors
- Reactive Oxygen Species
- Thioxanthenes