A recent study, titled “A NPAS4-NuA4 Complex Couples Synaptic Activity to DNA Repair,” reveals an exciting new mechanism by which neurons maintain genomic stability in response to external stimuli. Published in Nature on February 23, 2023,1 this paper provides valuable insights into the molecular mechanisms underlying neurodegenerative diseases and brain aging that pave the way for the development of new therapeutic strategies. This commentary reviews the research findings and their potential for future applications. The brain is a highly dynamic and plastic organ that relies on neurons to modify their gene expression under a variety of pathophysiological conditions. Excessive or prolonged neuronal response to external stimuli can lead to DNA damage and genomic instability, thereby being harmful to the brain. Cumulative DNA damage in the neuronal genome is also a hallmark of neurodegeneration and brain aging. Until recently, the molecular mechanism by which neurons repair DNA and maintain genomic stability in response to external stimuli remained unclear. Neuronal PAS Domain Protein 4 (NPAS4) is an activity-induced transcription factor that is selectively expressed in neurons following membrane depolarization and subsequent calcium signaling. Through a series of biochemical and genomic experiments on mice, the researchers first determined that NPAS4 exists as part of a 21-protein complex called NPAS4-NuA4. They then measured DNA damage using γH2AX ChIP-seq, sBLISS-seq, END-seq and SAR-seq, which indicated that NPAS4 preferentially binds to active DNA breaking-induced sites in neurons. These advanced techniques can be used to analyze the binding sites of transcription factors,2 provide whole-genome maps with DNA double-strand breaks,3 monitor DNA terminal excision,4 and localize DNA repair synthesis in vivo and in various cell types.5 Thus, they could contribute greatly to future research in neuroscience and other biomedical fields. In addition, the NPAS4-NuA4 complex serves as a critical mediator in the mechanism underlying neurodegenerative diseases and aging in the brain. Activated in response to neuronal activity driven by changes in sensory experience, NPAS4-NuA4 binds to periodically damaged transcriptional regulatory elements and recruits DNA repair machinery to prevent age-dependent somatic mutation accumulation. Furthermore, impaired NPAS4-NuA4 leads to a range of cellular defects that result in a shortened lifespan, including dysregulation of neuronal activity-dependent transcriptional responses, loss of somatic inhibition of pyramidal neurons, impaired localization of protective repair machinery, and genomic instability. One of the most exciting aspects of this study is its discovery of a link between damage and neuronal activity-dependent regulatory elements and neuronal dysfunction in neurodegenerative diseases. Preventing mutations in the NPAS4-NuA4 complex during neurodevelopment and carefully balancing the proper ratio of excitatory and inhibitory neurons are key to sustaining neuronal survival. This conclusion suggests a new avenue for the development of drugs for Alzheimer's and Parkinson's diseases that target the NPAS4-NuA4 complex and its molecular pathways. The research also provides insight into the complex interplay between gene expression and DNA repair in aging. By targeting the DNA of hippocampal neurons in mice of different ages, researchers found that gene regulatory elements to which NPAS4–NuA4 binds are partially protected against age-dependent accumulation of somatic mutations. This finding suggests that promoting the protection of those recurrently broken sites can help maintain genome integrity and thus prevent mutation. It is worth considering whether all cell types in the body (i.e., beyond neurons) may regulate transcriptional activity, protect vulnerable DNA sites, and maintain genomic stability according to the type of stimulation they receive. There may be activity-dependent protective mechanisms for genome stability that remains unknown and thus need to be explored. Moreover, the unique repair mechanism proposed in this paper was based on mouse models and has not yet been verified in the human nervous system. If this could be explored in humans, the functions and upstream regulatory mechanisms of various protein components of the NPAS4-NuA4 complex could be further clarified to provide a better understanding of the occurrence and development of neurodegeneration. In conclusion, this study demonstrates the complex interplay between neuronal activity, gene expression, and DNA repair in the brain. Its findings broaden our knowledge of the pathogenesis of neurodegenerative diseases and aging in the brain and contribute to the field of neuroscience with important implications for the development of novel therapeutic approaches. Conglin Wang: Writing – original draft. Xintong Ge: Writing – original draft; Writing – review & editing. Wenqiang Xin: Writing – review & editing. Ping Lei: Writing – review & editing. This research was supported by Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0048), the National Natural Science Foundation of China (82271401, 82071394, 82072166), Science and Technology Foundation of Tianjin (21JCYBJC01180), and Science and Technology Project of Tianjin Municipal Health Commission (TJWJ2021QN005). The authors declare no conflicts of interest.
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