Neuronal enhancers are hotspots for DNA single-strand break repair

Wu, Wei; Hill, Sarah E.; Nathan, William J.; Paiano, Jacob; Callén, Elsa; Wang, Dongpeng; Shinoda, Kenta; Wietmarschen, Niek van; Colón-Mercado, Jennifer M.; Zong, Dali; Pace, Raffaella De; Shih, Han-Yu; Coon, Steven; Parsadanian, Maia; Pavani, Raphael Souza; Hanzlíková, Hana; Park, Solji; Jung, Seol Kyoung; McHugh, Peter J.; Canela, Andrés; Chen, Chongyi; Casellas, Rafael; Caldecott, Keith W.; Ward, Michael E.; Nussenzweig, André

doi:10.1038/s41586-021-03468-5

Cited by 162 publications

(193 citation statements)

References 80 publications

(43 reference statements)

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“…Most of the studies examining mechanisms of DNA damage in ALS have used 2D cell culture models, which are inherently limited at capturing the complexity of in vivo systems, and the field would benefit from using more relevant models, such as 3D organoid cultures [215]. In addition, many of the studies described in this review have used low-resolution methods to study DNA damage in ALS, and none so far have attempted to profile DNA damage across the genome, as has been done recently in neurons [216]. Increased DNA damage in ALS cells could occur through two general mechanisms: DDR dysfunction or increased DNA damage agents.…”

Section: Discussionmentioning

confidence: 99%

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

Kok

Palminha

Souza

et al. 2021

Cell. Mol. Life Sci.

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Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.

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Section: Discussionmentioning

confidence: 99%

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

Kok

Palminha

Souza

et al. 2021

Cell. Mol. Life Sci.

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“…To determine the role of AP-4 complex in regulating neuronal lysosome function and traffic in human neurons, we made use of the CRISPRi -i 3 iPSC system (Wu et al, 2021;Tian et al, 2019;Fernandopulle et al, 2018;Wang et al, 2017). In i 3 iPSCs, the neurogenic transcription factor NGN2 is integrated under a doxycycline-responsive promoter at a safe harbor locus in the WTC11 iPSC line (Fernandopulle et al, 2018;Wang et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…These i 3 Neurons exhibit morphological and biochemical properties of neurons 14 days post-induction (Gowrishankar et al, 2021;Wang et al, 2017) and are electrically active after 21 days (Wang et al, 2017). We have employed a modified i 3 iPSC system, in which CRISPR-inhibition (CRISPRi) machinery is integrated into a safe harbor locus (Wu et al, 2021;Tian et al, 2019). In CRISPRi, an enzymatically dead Cas9 fused to a KRAB transcriptional repressor is targeted close to the transcriptional start site of the target gene by a single guide RNA (sgRNA), thereby inhibiting expression of the gene.…”

Section: Resultsmentioning

confidence: 99%

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network

Majumder

Edmison

Rodger

et al. 2021

Preprint

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The adaptor protein complex-4 or AP-4 is known to mediate autophagosome maturation through regulating sorting of transmembrane cargo such as ATG9A at the Golgi. There is a need to understand AP-4 function in neurons, as mutations in any of its four subunits cause a complex form of hereditary spastic paraplegia (HSP) with intellectual disability. While AP-4 has been implicated in regulating trafficking and distribution of cargo such as ATG9A and APP, little is known about its effect on neuronal lysosomal protein traffic, lysosome biogenesis and function. In this study, we demonstrate that in human iPSC-derived neurons AP-4 regulates lysosome composition, function and transport via regulating export of critical lysosomal receptors, including Sortilin 1, from the trans-Golgi network to endo-lysosomes. Additionally, loss of AP-4 causes endo-lysosomes to stall and build up in axonal swellings potentially through reduced recruitment of retrograde transport machinery to the organelle. These findings of axonal lysosome build-up are highly reminiscent of those observed in Alzheimer disease as well as in neurons modelling the most common form of HSP, caused by spastin mutations. Our findings implicate AP-4 as a critical regulator of neuronal lysosome biogenesis and altered lysosome function and axonal endo-lysosome transport as an underlying defect in AP-4 deficient HSP.

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“…It is notable that cluster 6 contains several factors associated with PARP1 activity (e.g. the PARP1 binding protein (PARPBP) and BRCA1) that link this cluster to the repair of SSBs which are enriched at neuronal enhancers in post-mitotic neurons 72 . A further example is the regulation of autophagy initiation by PD-SNPs, highlighted in cluster 8.…”

Section: Discussionmentioning

confidence: 99%

Establishing gene regulatory networks from Parkinson’s disease risk loci

Farrow

Schierding

Gokuladhas

et al. 2021

Preprint

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The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent single nucleotide polymorphisms (SNPs) across 78 genomic regions associated with Parkinson's disease (PD), yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with PD-SNPs, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 PD-SNPs across 49 tissues, that encompass 36 peripheral and 13 CNS tissues. Notably, one third of these genes were regulated via trans- acting mechanisms (distal; risk locus-gene separated by > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and PD GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of PD. Through utilising Louvain clustering we extracted nine significant and highly intra-connected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with PD. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of PD-SNPs, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of PD.

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Neuronal enhancers are hotspots for DNA single-strand break repair

Cited by 162 publications

References 80 publications

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network

Establishing gene regulatory networks from Parkinson’s disease risk loci

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