Pollina EA, Gilliam DT, Landau AT, Lin C, Pajarillo N, Davis CP, Harmin DA, Yap EL, Vogel IR, Griffith EC, Nagy MA, Ling E, Duffy EE, Sabatini BL, Weitz CJ, Greenberg ME. A NPAS4-NuA4 complex couples synaptic activity to DNA repair. Nature. 2023 Feb;614(7949):732-741. Epub 2023 Feb 15 PubMed.

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  1. This study identified a DNA repair mechanism involving the NPAS4–NuA4 complex, which is specific for activated neurons. This fundamental study covers function of long-lived neurons from multiple angles and is important for understanding the factors responsible for genome integrity during aging. It includes the observation that NPAS4-NuA4-bound sites are relatively protected against the accumulation of somatic mutations. The results of the study contribute to a better understanding of mechanisms of aging and point to a potential link with neurodegenerative disorders, for which aging is the strongest risk factor.

    It would be important to evaluate age-related expression and the epigenetic pattern of the genes encoding the NPAS4–NuA4 complex. For instance, the number of age predictors based on DNA methylation profile (reflecting biological aging) is rising due to their potential in predicting healthspan (Bergsma and Rogaeva, 2020). This is of note because EP400, a component of NuA4, is part of the epigenetic clock reported by Zhang et al. (2019). Several recent studies of neurodegenerative diseases revealed a link between clinical outcomes and acceleration of epigenetic clocks (Bergsma and Rogaeva, 2020; Tang et al., 2022). 

    References:

    Bergsma T, Rogaeva E. DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan. Neurosci Insights. 2020;15:2633105520942221. Epub 2020 Jul 21 PubMed.

    Zhang Q, Vallerga CL, Walker RM, Lin T, Henders AK, Montgomery GW, He J, Fan D, Fowdar J, Kennedy M, Pitcher T, Pearson J, Halliday G, Kwok JB, Hickie I, Lewis S, Anderson T, Silburn PA, Mellick GD, Harris SE, Redmond P, Murray AD, Porteous DJ, Haley CS, Evans KL, McIntosh AM, Yang J, Gratten J, Marioni RE, Wray NR, Deary IJ, McRae AF, Visscher PM. Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing. Genome Med. 2019 Aug 23;11(1):54. PubMed.

    Tang X, Gonzalez-Latapi P, Marras C, Visanji NP, Yang W, Sato C, Lang AE, Rogaeva E, Zhang M. Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease. Mov Disord. 2022 Sep;37(9):1831-1840. Epub 2022 Aug 3 PubMed.

    View all comments by Ekaterina Rogaeva

  2. This elegant, multidisciplinary paper identifies a new activity-dependent NPAS4-NuA4-Tip60 complex that modulates neural circuitry and gene expression, and maintains genome stability. The findings add a new dimension to our understanding of genome maintenance in neurons, and raise interesting questions about how a breakdown in this process might affect neural circuits underlying cognition and the pathogenesis of age-related neurodegenerative disorders. The new findings advance previous observations that transient DNA damage, typically mediated by topoisomerase, is a component of transcription initiation. This process is fraught in postmitotic neurons that do not have the advantage of homologous recombination to mop up unrepaired DNA breaks. DNA damage in postmitotic neurons has been thought to be mediated primarily by non-homologous end joining (NHEJ); it will be interesting to explore the relationship of the new complex to the NHEJ machinery, and whether similar complexes, not necessarily containing NPAS4, participate in transcription-coupled repair in non-neuronal cells.

    NHEJ is an error-prone mechanism of DNA repair that may contribute to the accumulation of mutations with age in postmitotic cells. In this regard, a higher rate of mutations was observed at NPAS4-bound sites relative to non-bound sites in young animals, raising the possibility that repair by this complex is also error-prone. Despite this, the mutational frequency at NPAS-4-bound sites appears to decline significantly with age (Fig. 5e). Could this reflect a contraction in NPAS-4 binding sites with age, a change in neural circuit firing patterns, or a change in the biochemistry of DNA repair in aging neurons? Whatever the explanation, the role of the complex in genome integrity and gene regulation during aging is likely to be complex. 

    Might this complex play a role in age-related degeneration in the brain? Interestingly, we have previously demonstrated that the amyloid precursor protein (APP) can signal to the nucleus via TIP60, an integral component of the newly identified NPAS4-NuA4-Tip60 complex (Hass and Yankner, 2005). This signaling pathway was mediated by intact transmembrane APP rather than γ-secretase cleavage of APP to Aβ, and predicted that APP cleavage might actually interfere with TIP60 function. An intriguing possibility is that APP, which is integral to the pathology and genetics of Alzheimer’s disease, might modulate the activity or function of the NPAS4-NuA4-Tip60 complex.

    The role of genome integrity in Alzheimer’s disease and other age-related neurodegenerative disorders is unresolved. It may be informative, in this regard, to consider studies of humans exposed to high doses of radiation. Long-term studies of the Hiroshima atomic bomb survivors show that they are not associated with accelerated age-related cognitive decline or dementia, regardless of the age of the patient at the time of radiation exposure (Yamada et al., 2009, 2016). Moreover, patients who receive brain X-ray therapy for cancer can develop cognitive deficits, but this differs from Alzheimer’s disease both clinically and pathologically.

    It is possible, however, that single, high-dose exposure to radiation is mechanistically different in terms of DNA repair than a continuous breakdown in genome stability with age. The authors note that several components of the NPAS4-NuA4 complex are mutated in neurodevelopmental disorders. It would be of interest to explore whether genetic variants in this pathway predispose to age-related neurodegeneration.

    References:

    Hass MR, Yankner BA. A {gamma}-secretase-independent mechanism of signal transduction by the amyloid precursor protein. J Biol Chem. 2005 Nov 4;280(44):36895-904. PubMed.

    Yamada M, Kasagi F, Mimori Y, Miyachi T, Ohshita T, Sasaki H. Incidence of dementia among atomic-bomb survivors--Radiation Effects Research Foundation Adult Health Study. J Neurol Sci. 2009 Jun 15;281(1-2):11-4. PubMed.

    Yamada M, Landes RD, Mimori Y, Nagano Y, Sasaki H. Radiation Effects on Cognitive Function Among Atomic Bomb Survivors Exposed at or After Adolescence. Am J Med. 2016 Jun;129(6):586-91. Epub 2015 Oct 22 PubMed.

    View all comments by Bruce Yankner

  3. Early studies revealed that etoposide-induced DSBs stimulated transcription of a program of immediate early genes such as FOS. DNA DSBs were subsequently observed in normal mice stimulated with fear or light in the same genes. Although DSBs were classically associated with toxicity and disease states such Alzheimer’s, collectively, these seminal studies established that DSBs could occur in the brains of normal animals. Pollina et al. now provide powerful evidence that a neuron-specific NPAS4-NUA4 chromatin complex couples synaptic activity-dependent transcription with DNA damage and repair at stimulated transcripts. The analysis is comprehensive. Knock-in mice expressing HA- and FLAG-tagged NPAS4 and NUA4 allow direct visualization by immunofluorescence, indicating that the two proteins co-localize in neurons. A physical complex between NPAS4 and NUA4 was established in vitro using IP, column chromatography, and mass spectrometry, and in vivo at genomic sites identified by cut-and-run analysis and chromatin-IP.

    These convincing studies suggested that NPAS4-NUA4 assembles on chromatin in neurons in an activity-dependent manner. Although the NPAS4-NUA4 complex in other systems is known to stimulate transcription and to play a role in DNA repair, the surprise was that NPAS4-NUA4 dually induced transcription in response to neuronal stimulation and simultaneously protected those sites from DNA damage. A robust set of mapping approaches, including sBLISS and ENDSeq, confirmed that DSBs formed downstream of stimulation in genes within their promoters.

    In general, the set of studies from Pollina et al. provide a tour de force of technical data to support the idea that synaptic stimulation of key transcripts and their protection from damage are linked functions. A protection system seems logical. Neurons must survive for years and must retain the integrity for synapse activation and the requisite stimulation of essential gene programs without damage. Indeed, this duality appears to be an essential process since the authors show that disruption of the NPAS4-NUA4 complex reduces lifespan.

    There are reasonable gaps and additional questions raised in the analyses. For example, the authors demonstrate a dual role of NPAS4-NUA4 for a specific group of stimulated transcripts, which were preselected for harboring NPAS4-NUA4 binding sites. Since not all genes contain NPAS4-NUA4 binding sites, Pollina et al. may have opened the door to a general coupling mechanism that has shared properties with other yet-to-be characterized chromatin complexes and may influence a distinct set of transcripts that are stimulated by different conditions. Minimally, the function-protection cycle provides a general model by which activity is accompanied with a built-in protection mechanism.

    While the authors clearly show the activity-dependent stimulation and repair functions of NPAS4-NUA4 were neuronal functions, it remains to be seen whether there are coupled events in astrocytes, which were not examined in these analyses. Astrocytes are intimately involved in calcium signaling. It may be that stimulation has an impact on transcript programs in astrocytes that have different kinetics and/or regulate neuronal stimulation but are masked in this study. The mechanisms by which DSBs form remains to be elucidated. There are multiple DNA DSBR complexes in these brains, and which ones are present and their machinery is, as yet, poorly understood.

    Collectively, however, this work provides a compelling mechanism by which cells work out an efficient way to maintain transcript stimulation and transcript integrity during synaptic activity. Disease toxicity in Alzheimer’s may arise from interference of these protections.

    View all comments by Cynthia McMurray

  4. Very exciting insights into activity-dependent DNA repair. Interestingly, we have recently discovered that, in addition to chromatin-associated mechanisms, Tip60 (KAT5) also doubles as an RNA splicing modulator. In our paper published in the Journal of Neuroscience, we propose a switching mechanism for Tip60 that allows it to regulate histone acetylation as well as splicing modulation of a similar set of Alzheimer's disease-enriched gene targets to control not only which genes are activated, but also how they are ultimately spliced for appropriate protein function.

    Additionally, we show that loss of Tip60 in Alzheimer's disease model brain interferes with the splicing modulation function and may underlie some of the splicing defects detected in the postmortem Alzheimer’s patient brains. I speculate that Tip60 supports both DNA repair and splicing modulation at the sites of transcription, and that these processes go awry in the early stages of disease progression.

    References:

    Bhatnagar A, Krick K, Karisetty BC, Armour EM, Heller EA, Elefant F. Tip60's Novel RNA-Binding Function Modulates Alternative Splicing of Pre-mRNA Targets Implicated in Alzheimer's Disease. J Neurosci. 2023 Mar 29;43(13):2398-2423. Epub 2023 Feb 27 PubMed.

    View all comments by Akanksha Bhatnagar

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