. Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature. 2018 Nov;563(7733):639-645. Epub 2018 Nov 21 PubMed.

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  1. In this truly remarkable ground-breaking study, the Jerold Chun group conclusively demonstrate a totally unexpected cause of genomic variability in the human brain: the incorporation of abnormal forms of the APP gene apparently reverse-transcribed from mRNA, missing introns, with novel inter-exonic junctions, and “point mutations” found in familial Alzheimer’s. The study uses numerous methods to support the findings, which are restricted to neurons and less prevalent or absent in controls, and convincingly shows an increase in these novel DNA insertions with age in a mouse model.

    This study provides a potential mechanism leading to Alzheimer’s disease, which could even apply to other age-related neurodegenerative disorders, like PD, and studies in these will need to consider this possibility. This work also gives fundamental insights into the brain genome, which is clearly much more plastic than previously thought. The lead author has been a pioneer in this field for over 25 years, and this is building on the previous demonstration of increased APP exon copies in Alzheimer’s neurons, which have now been explained, mosaic aneuploidy, and common “conventional” CNVs arising in development of mouse neurons. Further work is needed to show whether other genes are affected, as presenilin-1 was not, or whether this phenomenon is mostly restricted to APP, and why this would be so. The authors even highlight the potential of anti-retroviral drugs to combat this attack on the neuronal genome.

    View all comments by Christos Proukakis
  2. In a very thoughtful and well-designed set of experiments, Jerold Chun’s team further advances our knowledge of neuronal mosaicism and its possible relevance to brain function and disease. DNA replication must be extremely well-controlled and precise in order to facilitate accurate transfer of genetic information during cell division. Yet in the brain, where cell division occurs on a very limited basis, the observation of neuronal DNA recombination via reverse transcription not only provides a mechanistic explanation for the mosaicism that has been previously observed in neurons, but also allows for diversification of each neuron’s unique protein repertoire over its long lifespan.

    Besides the discovery of a potential mechanism for neuronal DNA recombination, the finding that this mechanism is linked to neuronal activity and may play a role in AD pathogenesis is intriguing. In Down's syndrome (DS), chromosomal mosaicism resulting in aneuploidy of chromosome 21 (acquisition of a third copy of the APP gene), is thought to be the main pathogenic pathway to AD. Indeed, individuals with DS who are disomic for APP do not develop AD. Whether APP mosaicism is a cause for, or consequence of, AD pathogenesis in the sporadic population remains to be definitively established, but the work of Chun's lab raises the possibility that genetic recombination may play an important role in AD while opening up new avenues in fundamental neuroscience research.

    View all comments by Michael Rafii
  3. This exciting paper describes a new mechanism for generating genetic diversity in the brain, apparently acquired during life, especially in Alzheimer’s disease, and provides insight into how this may be related to neurodegenerative disease. It is a next view on the RNA world (e.g. Wang et al., 2014; Gout et al., 2017).

    Accumulating evidence indicates that the brain is a genetic mosaic. Cell-to-cell genomic differences, which appear to be the result of somatic mutations during development and aging, contribute to cellular diversity in the nervous system. Interestingly, it has been shown that this mosaicism can also contribute to diseases of the brain (Verheijen et al., 2018). How these somatic mutations arise in nervous tissue remains largely unknown.

    Previous work by the same group has found that neurons in sporadic AD patient brains contain more copies of APP (Bushman et al., 2015), a gene demonstrated to be causally involved in autosomal-dominant AD cases. Now, the authors provide a compelling explanation for this phenomenon: In their paper they show mosaic incorporation of many APP variants by error-prone reverse transcription, potentially resulting in toxic proteins and thereby contributing to sporadic AD. If confirmed by other research groups, this data adds a new layer of complexity to AD and potentially to neurobiology in general.

    The study raises many questions:

    • Although it is mentioned that the APP variants are translated into proteins, further experimental confirmation in postmortem AD tissue is needed. It has been demonstrated previously that specific antibodies can be used to detect APP mutant proteins in neurons of AD brains (van Leeuwen et al., 1998). 
    • How do the mutant APP proteins confer toxicity? The authors express some mutant APPs in a cell line, but it would be interesting to see the effects on human stem cell-derived neurons or in an in vivo model. It will be important to incorporate the findings into a relevant model system that includes other cell types (De Strooper and Karran, 2016). 
    • Are these recombination events a cause or consequence of neurodegeneration in AD? If these events occur early, can they provide new clues about AD etiology? Only few AD cases are “familial.” What drives the APP recombinations? Are there genetic risk factors? Are there environmental triggers (e.g., physical trauma, exposure to toxins, infectious agents, early life stress)?
    • Does the mechanism apply to other genes, and can it be linked to other diseases, e.g. Parkinson’s or amyotrophic lateral sclerosis?

    The findings by Lee et al. provide a basis for new work on AD biology, a field that desperately needs new ideas (Morris et al., 2018). 

    References:

    . RNA-DNA differences are generated in human cells within seconds after RNA exits polymerase II. Cell Rep. 2014 Mar 13;6(5):906-15. Epub 2014 Feb 20 PubMed.

    . The landscape of transcription errors in eukaryotic cells. Sci Adv. 2017 Oct;3(10):e1701484. Epub 2017 Oct 20 PubMed.

    . Somatic mutations in neurons during aging and neurodegeneration. Acta Neuropathol. 2018 Jun;135(6):811-826. Epub 2018 Apr 28 PubMed.

    . Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains. Elife. 2015 Feb 4;4 PubMed.

    . Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.

    . The Cellular Phase of Alzheimer's Disease. Cell. 2016 Feb 11;164(4):603-15. PubMed.

    . Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathol. 2018 Nov;136(5):663-689. Epub 2018 Oct 22 PubMed.

    View all comments by Fred van Leeuwen
  4. This groundbreaking article suggests that APP somatic recombination represents a novel pathogenic mechanism potentially contributing to Alzheimer’s disease. This work has extremely interesting implications for brain functional genomics in general. However, replication studies are needed and many questions remain.

    As Lee et al. note, somatic DNA recombination has not been previously described in the human brain. Nevertheless, their findings fit into an emerging framework indicating neurodegeneration is characterized by increased neural genomic instability. Neuronal hyperploidy (DNA content higher than in normal somatic cells) is raised in the early to mid-stages of AD before dropping later in disease, consistent with aberrant cell cycle re-entry preceding neuronal death (Arendt et al., 2010; Yang et al., 2001). Elevated DNA damage is observed in the C9ORF72-linked amyotrophic lateral sclerosis (ALS) spinal cord (Walker et al., 2017). Aging, one of the strongest risk factors for AD, increases the neuronal burden of somatic DNA variants present in some but not all of an individual’s cells (Hébert et al., 2013; Lodato et al., 2018). Indeed this reflects the age-dependent APP gencDNA increase Lee et al. detected in the J20 mouse model.

    Lee et al. mention that APP gencDNAs are similar to but distinct from transposable elements (TEs). Interestingly, neurodegeneration-associated TE reactivation has been described in animal models of pathological proteins and in human brain tissue from the diseases in which they aggregate. Examples include tau, AD, and progressive supranuclear palsy (Guo et al., 2018; Sun et al., 2018); TDP-43, ALS, and frontotemporal dementia (Douville et al., 2011; Krug et al., 2017; Prudencio et al., 2017). 

    The presence of myriad neuronal APP gencDNA variants could have a range of complex effects on AD pathogenesis. An obvious implication is that increased APP gencDNA copies could elevate expression of their encoded proteins, ultimately raising amyloid-β levels. One intriguing possibility is whether these variants contribute to the stereological progression of pathology observed in AD (Montine et al., 2012). This could be investigated by quantifying APP gencDNA burden in different brain regions.

    The article raises other important questions. Given the apparent importance of DNA lesions for APP somatic recombination, what mechanisms drive increased DNA strand breaks observed in AD (Mullaart et al., 1990) or APP transgenic mice (Suberbielle et al., 2013), e.g., neuronal activity (Madabhushi et al., 2015) or impaired DNA repair (Katyal and McKinnon, 2008)? Are gencDNA-encoded proteins expressed in vivo? Given the critical role glia play in mediating AD genetic risk (Huang et al., 2017; Sims et al., 2017), do neuronal-glial interactions influence neuronal APP somatic recombination?

    The broader implications are exciting. In the human brain under normal physiological conditions, how many genes undergo somatic recombination, and how frequently? If only a subset of genes do, what sets them apart? This phenomenon could endow the brain with an additional physiological layer of transcriptomic control, in which previous gene expression experience dynamically sculpts neuronal transcriptomes to reinforce specific cellular states most effective for specific neural networks.

    Why did neural somatic recombination evolve? One fascinating speculation is that somatic recombination could provide a selective mechanism operating at the neuronal cell level, whereby a constellation of gencDNA variants are generated across a cell population, and neurons whose genomes most benefit their neural network survive and remain integrated.

    References:

    . Selective cell death of hyperploid neurons in Alzheimer's disease. Am J Pathol. 2010 Jul;177(1):15-20. PubMed.

    . DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001 Apr 15;21(8):2661-8. PubMed.

    . C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017 Sep;20(9):1225-1235. Epub 2017 Jul 17 PubMed.

    . Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013 May 7;80(19):1778-83. PubMed.

    . Aging and neurodegeneration are associated with increased mutations in single human neurons. Science. 2018 Feb 2;359(6375):555-559. Epub 2017 Dec 7 PubMed.

    . Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci. 2018 Aug;21(8):1038-1048. Epub 2018 Jul 23 PubMed.

    . Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol. 2011 Jan;69(1):141-51. PubMed.

    . Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 2017 Mar;13(3):e1006635. Epub 2017 Mar 16 PubMed.

    . Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum Mol Genet. 2017 Sep 1;26(17):3421-3431. PubMed.

    . National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 2012 Jan;123(1):1-11. PubMed.

    . Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients. Neurobiol Aging. 1990 May-Jun;11(3):169-73. PubMed.

    . Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat Neurosci. 2013 May;16(5):613-21. PubMed.

    . Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell. 2015 Jun 18;161(7):1592-605. Epub 2015 Jun 4 PubMed.

    . A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci. 2017 Aug;20(8):1052-1061. Epub 2017 Jun 19 PubMed.

    . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.

    View all comments by Alan Renton
  5. Lee et al. describe somatic mosaicism leading to increased copy number of the APP gene as a novel mechanism for amplified Aβ synthesis. This finding is consistent with the impact of triplication of the APP gene causing AD in Down’s syndrome and is supportive of Aβ lowering for AD prevention. Novel APP derived genomic cDNAs (gencDNAs) are also described as a source of APP-derived proteins that may contribute to neuronal toxicity. Some of these novel toxic proteins are predicted to be independent of β- and γ-secretase activity and so would not be impacted by inhibitors of these enzymes. This important new APP-related pathway for cell toxicity requires substantially more validation in human AD patients, tissues, and relevant cell lines to understand its relative contribution to the overall neuropathological cascade leading to AD. The potential elevation of somatic mosaicism with aging to be a common mechanism of neurodegeneration deserves intensive investigation for possible mechanisms of therapeutic interventions.

    View all comments by Matthew Kennedy

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