DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms

DNA Repair 81 (2019) 102669

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Review Article

DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms☆,☆☆

T

Arwa A. Abugablea,b,1, Julia L.M. Morrisa,1, Nelma M. Palminhaa,1, Ringaile Zaksauskaitea,1, ⁎ ⁎ Swagat Raya, , Sherif F. El-Khamisya,b, a b

Healthy Lifespan Institute, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK Center of Genomics, Helmy Institute, Zewail City of Science and Technology, Giza, Egypt

ARTICLE INFO

ABSTRACT

Keywords: DNA repair Neurological disease TDP Alzheimer Parkinson ALS Dementia Huntington Nucleotide repeat expansion

In both replicating and non-replicating cells, the maintenance of genomic stability is of utmost importance. Dividing cells can repair DNA damage during cell division, tolerate the damage by employing potentially mutagenic DNA polymerases or die via apoptosis. However, the options for accurate DNA repair are more limited in non-replicating neuronal cells. If DNA damage is left unresolved, neuronal cells die causing neurodegenerative disorders. A number of pathogenic variants of DNA repair proteins have been linked to multiple neurological diseases. The current challenge is to harness our knowledge of fundamental properties of DNA repair to improve diagnosis, prognosis and treatment of such debilitating disorders. In this perspective, we will focus on recent efforts in identifying novel DNA repair biomarkers for the diagnosis of neurological disorders and their use in monitoring the patient response to therapy. These efforts are greatly facilitated by the development of model organisms such as zebrafish, which will also be summarised.

1. Introduction The accumulation of DNA damage has been reported in aged brains and in pathological brain tissues [1]. Several DNA repair pathways are known to be dysregulated in various neurological disorders. Although there is strong evidence in the literature that relates defects in DNA damage repair with different neurological disorders, it is yet unclear whether these defects are a cause or an effect of the pathological condition of the brain [1]. DNA damage is known to contribute significantly to cellular dysfunction and death. Defective DNA repair pathways lead to genomic instability in post-mitotic cells such as neuronal tissue, causing neurodegenerative disorders [2]. Several reviews have highlighted the link between the different neurological disorders and defects in key players in the DNA repair pathways, as summarised in Table 1 [3–10]. The aforementioned table highlights the pathogenic variants of key DNA repair markers that are linked to various neurological disorders. However, it does not exclude the role of several other DNA repair proteins

involved in the pathogenesis of proteinopathy-mediated neurodegenerative disorders and ageing, which is highlighted in the sections below and outlined in Fig. 1. The early detection and monitoring of such disorders demand the identification of reliable biomarkers. This area of research is rapidly evolving as novel biomarkers implicated in different pathways are being investigated in various clinical specimens [87,88]. These developments will enable differential diagnosis, precise monitoring of disease progression as well as discovery of new treatment modalities. Throughout this perspective, we will refer to examples of neurodegenerative and ageing disorders, their underlying molecular mechanisms, model organisms as well as potential biomarkers for diagnosis. 2. Alzheimer’s disease Alzheimer’s Disease (AD) is a progressive, neurodegenerative disease that affects approximately 47 million individuals worldwide [89]. This figure is expected to increase to 74.7 million by 2030 [89]. It is characterised by memory and cognition impairment, loss of neurons

Abbreviations: DDR, DNA damage repair; SCAN1, Spinocerebellar ataxia with axonal neuropathy 1; AD, Alzheimer’s Disease; PD, Parkinson’s Disease; ALS, Amyotrophic lateral sclerosis; HD, Huntington’s disease; TOP1, topoisomerase 1; TDP, tyrosyl DNA phosphodiesterase; PDBs, protein-linked DNA breaks ☆ This Special Issue is edited by Philip C. Hanawalt. ☆☆ This article is part of the special issue Cutting-edge Perspectives in Genomic Maintenance VI. ⁎ Corresponding authors at: Healthy Lifespan Institute, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK. E-mail addresses: [email protected] (S. Ray), [email protected] (S.F. El-Khamisy). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.dnarep.2019.102669

Available online 08 July 2019 1568-7864/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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Table 1 Mutated DNA repair genes and their associated neurological disorders. Mutated gene

Defective DNA repair pathway

Associated neurological disease

ERCC6/CSB [11], ERCC2/XPD [12], ERCC5/XPG [13], ERCC1 [14] ERCC8/CSA [15,16], ERCC6/CSB [15,16,17], XPB [15,16], XPD [15,16] and XPG [15] ERCC3/XPB [15,16], ERCC2/XPD [15,16,18,19], TTDA [20,21] XPA [15], XPB [15,16], XPC [15], XPD [15,16,18,19], XPE [15], XPF [15], XPG [15], POLH [22] XPF [23]

Transcription coupled - nucleotide excision repair (TC-NER)

Cerebro-oculo-facio-skeletal syndrome (COFS) Cockayne syndrome (CS)

Nucleotide excision repair (NER)

Trichothiodystrophy (TTD) Xeroderma pigmentosum (XP)

FANCA [24,25,26], FANCB [25,26], FANCC [27,28], FANCD1/BRCA2 [29], FANCD2 [24,25,26], FANCE [24,25,26], FANCF [24,25,26], FANCG [24,25,26], FANCI [25,26], FANCJ/BRIP1 [30], FANCL [31], FANCM [32], FANCN/PALB2 [33,34], FANCO/RAD51C [35], FANCP/SLX4 [36], XRCC2 [37], ERCC4 [25,38] TDP1 [39,40] XRCC1 [41] APTX [42,43] SETX [44,45] SOD1 [46], SETX [47], TARDBP [48,49,50], FUS [51,52] ATM [53,54] MRE11 [55,56,57] NBS1 [58,59] RAD50 [60] ATR [61,62], PCNT [63], RBBP8 [64] MCPH1 [10,65,66,67] LIG4 [68] XLF / NHEJ1 / Cernunnos [69,70] PNKP [71]

NER and inter-strand crosslink (ICL) repair ICL repair and homologous recombination (HR)

Single-strand break repair (SSBR) and oxidative stress

Double-strand break repair (DSBR), damage signalling and oxidative stress DSBR, damage signalling and replication fork repair Non-homologous end joining (NHEJ) NHEJ and SSBR

RBBP8 [64] RNF168 [72,73]

DSBR

BLM [74,75] WRN [76]

HR DNA replication forks, base excision repair (BER), NHEJ and HR Replication fork repair Telomere maintenance Replication stress, damage signaling and immunological response Mitochondrial DNA maintenance and oxidative stress

SMARCAL1 [77] DKC1 [78,79], TERC [80] RNASEH2 [81,82], TREX1 [83,84] POLG [85], TWINKLE [86]

and dementia. In AD brains, extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of fibrillar aggregates of hyperphosphorylated tau proteins are formed. Clinically, decreased levels of Aβ-42 in the cerebrospinal fluid (CSF) and increased levels of total and phosphorylated tau reflect deposition of amyloid plaques in the brain and neurodegeneration [90]. While ageing is one of the most prominent risk factors for AD, it is also associated with the accumulation of oxidative stress. Several reports hypothesize that increased oxidation of nucleic acids in brains results in neuronal dysfunction and neurodegeneration [91–93]. Increased oxidative DNA damage in AD is usually repaired via base excision repair (BER). BER, extensively reviewed by Wallace et al., is a single-strand break repair pathway which is responsible for the removal of structural abnormalities caused by oxidation, alkylation, deamination or depurination [94]. When the damage exceeds the repair, cellular senescence, genome mutation or apoptosis takes place, which tend to occur more frequently in the aged brain [95–97]. The expression level of BER genes was investigated in post-mortem brain tissue, CSF and blood samples in healthy controls (HC) and patients with AD or mild cognitive impairment (MCI). The mRNA levels of 8-oxoguanine DNA glycosylase (OGG1) were reduced, whilst the mRNA levels of poly (ADP-ribose) polymerase 1 (PARP1) were increased in the blood of MCI and prodromal (early-stage) AD patients. This is regardless of their levels of Aβ-42 and tau proteins in the CSF. This, however, was not the case in HC, suggesting perturbed DNA repair in individuals susceptible to

XPF-ERCC1 (XFE) progeroid syndrome Fanconi anemia (FA) – microcephaly

Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) Spinocerebellar ataxia, autosomal recessive 26 (SCAR26) Ataxia with oculomotor apraxia-1 (AOA1) Ataxia with oculomotor apraxia-2 (AOA2) Amyotrophic lateral sclerosis (ALS) Ataxia telangiectasia (AT) Ataxia telangiectasia like disease (ATLD) Nijmegen breakage syndrome (NBS) Nijmegen breakage syndrome-like disorder (NBSLD) Seckel syndrome (SS) Primary microcephaly LIG4 syndrome XLF syndrome Microcephaly, intractable seizures and developmental delay syndrome (MCSZ) Jawad syndrome RNF168-deficiency syndrome; radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties syndrome (RIDDLE Syndrome) Bloom syndrome (BS) Werner syndrome (WS) Schimke immunoosseous dysplasia (SIOD) Dyskeratosis congenital (DKC) Aicardi Goutieres syndrome (AGS) Spino-cerebellar ataxia-epilepsy syndrome (SCAE) or sensory ataxic neuropathy, dysarthria and opthalmoparesis (SANDO)

developing AD [98]. These results were obtained via venepuncture, a non-invasive method, and as such, OGG1 and PARP1 have the potential to be applied clinically as biomarkers for the early diagnosis of AD [98]. Nuclear DNA damage can potentially upregulate the expression of these DNA damage proteins. Since these biomarkers are also elevated in nonAD dementia, their specificity and sensitivity in other types of dementia are yet to be investigated [99]. Increased PARP1 levels have been shown to increase the activation of AMP protein kinase (AMPK). This contributes to the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, leading to caspase independent necrotic cell death [100]. In addition, activated p53 has been shown to be stabilised by PARylation which leads to increased cell death due to the upregulation of pro-apoptotic protein expression (Fig. 1A) [101]. 3. Parkinson’s disease Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after AD, affecting more than 3% of the population over 80 years of age [102–104]. Patients with this disease show loss of neurons in the substantia nigra and intracellular Lewy bodies, which are primarily made up of α-synuclein aggregates [102]. The main symptoms of PD are tremors, bradykinesia (slowness of movement) and muscle stiffness. These symptoms usually start after 50 years of age [105]. DNA repair defects promote the onset of major PD pathogenesis 2

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Fig. 1. Defective DNA repair is a common feature of multiple neurodegenerative disorders. (A) Overactivation of PARP1 leads to increased activation of AMP protein kinase (AMPK). This contributes to the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, causing DNA fragmentation and leading to caspase independent necrotic cell death or parthanatos. In Alzheimer’s disease (AD), activated p53 is stabilised by PARylation. Activated p53 accumulates in the nucleus and causes cell death through the upregulation of pro-apoptotic protein expression. (B) Dipeptide repeat (DPR) proteins expressed from G4C2 expansions cause pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) by overlapping mechanisms: in one hand, DPRs causes defects in ataxia telangiectasia mutated (ATM) signalling, which promotes accumulation of topoisomerase 1 (TOP1)-linked DNA breaks. ATM deficiency is also responsible for impaired non-homologous end-joining (NHEJ) repair. Additionally, DPR aggregates are associated with defects in proteasome degradation. Insufficient protein degradation is accompanied by accumulation of the autophagy protein, p62. Accumulation of p62 aggregates are responsible for sequestering and inhibiting RNF168, an E3 ubiquitin ligase responsible for ubiquitinating histone H2A during DSB repair. RNF168-mediated ubiquitination of H2A is necessary for the recruitment of the NHEJ protein 53BP1. Thus, defects in RNF168 activity caused by p62 accumulation lead to lack of 53BP1 recruitment during DSB repair and consequent NHEJ deficiency. Defects in NHEJ repair are also caused by mislocalisation and aggregation of TDP-43, a hallmark in ALS/FTD. Impaired TDP-43 signalling causes deficient recruitment of NHEJ downstream proteins, ligase 4 (LIG4) and XRCC4, leading to accumulation of unrepaired DSBs. (C) In Parkinson’s disease (PD), increased PARP1 has been shown to lead to the acceleration of α-synuclein (syn) fibrillisation, vastly increasing its cytotoxicity. (D) Also in Parkinson’s disease, α-synuclein has been shown to activate NHEJ repair pathway, as shown by the increased levels of ATM, yH2AX and 53BP1. (E) In Huntington’s disease elevated PARP1 levels are often observed. Increased PARP1 activation in HD cells leads to increased AMPK activation with consequent mitochondrial release of AIF, which promotes cell death by parthanatos. Elevated AMPK signalling also decreases the levels of the cAMP response element-binding protein (CREB) transcription factor. CREB is a transcriptional regulator for the expression of survival genes, including rain derived neurotrophic factor (BDNF) and bcl-2. Therefore, insufficient CREB activity causes increased cell death. (F) Ruijs-Aalfs Syndrome arises due to germline mutations in Spartan which leads to an increase of unresolved protein-linked DNA breaks (PDBs). (G) In Huntington's patients, mutant huntingtin (mtHTT) impairs NHEJ by disrupting Ku70-Ku80 heterodimer formation and Ku70-DNA interaction. (*) The identification of novel diagnostic and prognostic biomarkers is of utmost importance for early detection, monitoring disease progression and possible therapeutic targeting. For example, PARP1 levels were found in the blood of prodromal AD patients. Additionally, poly-GP DPRs are frequently observed in pre-symptomatic ALS/FTD individuals, while elevated TDP-43 levels can be found in the CSF of ALS/FTD patients. In PD patients, PAR and α-synuclein can also be detected in the CSF.

hallmarks, such as mitochondrial dysfunction as well as perturbed dopaminergic system and protein quality control [102]. α-synuclein is the main link between reduced DNA repair and PD, and was recently shown to activate ataxia telangiectasia mutated (ATM), a major DNA damage repair (DDR) signalling kinase, and two of its substrates, phospho-histone H2AX (γH2AX) and p53-Binding Protein 1 (53BP1) (Fig. 1D) [106]. This activation was rescued by antioxidants, suggesting it was partly due to oxidative stress. PARP1 has also been recently reported to contribute to the

pathogenesis of PD [107]. Increased PARylation by PARP1 mediates the loss of dopaminergic neurons. Elevated poly (ADP-ribose) (PAR) seeds and accelerates the fibrillisation of α-synuclein, resulting in the formation of a more compact and misfolded protein with 25-fold higher toxicity (Fig. 1C). This increased toxicity was counteracted by the inhibition and depletion of PARP1. PAR and α-synuclein can be detected in the CSF while α-synuclein can also be found in other biological fluids, making them potential biomarkers for PD pathogenesis [107–109]. 3

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which would provide a more accurate insight on the levels of the brainspecific forms of TDP-43. There are several limitations that affect the quantification of TDP-43 in the CSF, which include its decreased concentration as well as the low affinity to TDP-43 antibodies in the presence of high concentrations of albumin and immunoglobulins [130]. Given the limited diagnostic accuracy and high variability in the quantification of TDP-43, its potential use as a biomarker requires further investigations [130]. In ALS/FTD patients carrying FUS mutations, FUS protein aggregates form stress granules in the cytoplasm of motor neuron cells, which is similar to TDP-43 proteinopathy [131]. Recent reports have shown a correlation between FUS aggregation and impaired DNA damage repair. FUS is recruited to DNA damage sites in a PARP1-dependent manner [131,132]. Mutations in the NLS of FUS result in increased DNA damage in the spinal cord of ALS patients [133]. These findings are in agreement with a recent study showing increased DSB markers in FUS-ALS neural cells. The increase in DNA damage precedes cytoplasmic aggregation of mutant FUS, indicating that defects in DDR mechanisms might cause FUS-ALS related phenotypes. Moreover, PARP1 inhibition diminished FUS recruitment to the DNA damage sites and induced FUS cytoplasmic mislocalisation and aggregation. Inhibition of poly (ADP-ribose) glycohydrolase (PARG), an enzyme that hydrolyses PAR chains, rescued FUS-ALS phenotypes by enhancing FUS recruitment to the damage sites and decreasing its cytoplasmic aggregation [131].

Table 2 Polynucleotide repeat expansion neurodegenerative disorders. Disease

Gene

Locus

WT repeat number

Mutant repeat number (full penetrance)

HD [134,136] SCA1 [134,135,136] SCA2 [134,135,136] SCA3 [134,135,136] SCA6 [134,135,136] SCA7 [134,135,136] SCA12 [134,135,136] SCA17 [134,135,136] SMBA [134,136] DRPLA [134,136] ALS/FTD [137]

HTT ATXN1 ATXN2 ATXN3 CACNA1A ATXN7 PPP2R2B TBP AR ATN1 C9orf72

4p16.3 6p22.3 12q24 14q32 19p13 3p14 5q32 6q27 Xq12 12p13 9p21.2

9-26 6-35 13-31 11-14 4-18 4-19 4-32 25-40 9-34 6-35 2-24

40-180 41-83 32-500 52-86 20-33 36-460 51-78 45-66 > 40 49-93 > 30

Furthermore, nucleotide excision repair (NER) is crucial for maintaining the integrity of the dopaminergic system [110]. PD patient fibroblasts have impaired NER capacity and mice with Ercc1 mutations exhibit defects in their dopaminergic neurons, mitochondrial dysfunction and increased α-synuclein phosphorylation. 4. Amyotrophic lateral sclerosis and frontotemporal dementia Amyotrophic lateral sclerosis (ALS) is a motor neuron disorder that affects around 3 in 100,000 individuals in Europe and the United States [111]. ALS is caused by the degeneration of lower and upper motor neurons in the spinal cord and motor cortex, respectively [112]. Frontotemporal dementia (FTD) is the second most common type of dementia after AD and affects the frontal and temporal lobes of the brain due to the degeneration of spindle neurons [113]. ALS and FTD share a common aetiology. ALS/FTD can arise from mutations in the TARDBP gene (encodes for the transactivation response DNA-binding protein "TDP-43"), fused in sarcoma (FUS), ubiquilin-2 (UBQLN2), p97/ valosin-containing protein (VCP), superoxide dismutase 1 (SOD1) and the gene encoding for sequestome 1/p62 (SQSTM1/p62), among others [114–116]. TDP-43 is a RNA/DNA binding protein involved in the regulation of RNA transcription, splicing and transport [117]. Additionally, a recent report has demonstrated the involvement of TDP-43 in double-strand break (DSB) repair. In neural cells, TDP-43 is recruited to DNA damage sites and interacts with proteins involved in non-homologous endjoining (NHEJ) repair, including 53BP1, Ku70, XRCC4 and LIG4 (Fig. 1B) [118]. Under physiological conditions, TDP-43 is predominantly localised in the nucleus. The nuclear localisation signal (NLS) and nuclear export signal (NES) domains allow its nuclear-cytoplasmic translocation [119]. Mislocalisation of TDP-43 is particularly toxic to neurons and was shown to be involved in the pathogenesis of ALS/FTD [120–122]. Mutations in TDP-43 cause its cytoplasmic relocation, nuclear depletion and aggregation into stress granules (Fig. 1B) [119]. The presence of cytoplasmic aggregates of misfolded TDP-43 in ubiquitinated inclusions is a common feature observed in 97% of ALS patients and nearly half of FTD patients [117,120,122,123]. TDP-43 proteinopathy is implicated in several neurodegenerative diseases [124]. Elevated TDP-43 levels were found in the plasma of ALS, FTD and AD patients compared to healthy and non-dementia controls [125–128]. The plasma levels in AD and FTD patients were found to be proportional to the levels in post-mortem brain tissue. However, the CSF levels of TDP-43 appear to differ among ALS patients, where lower levels are associated with poor prognosis [129,130]. Although TDP-43 is a ubiquitously expressed protein, the ALS/FTD pathological forms are exclusively expressed in the brain, which makes it difficult to detect in the blood due to the blood-brain barrier [120,130]. Conversely, the CSF is in direct contact with the brain,

5. Polynucleotide repeat disorders Several inherited neurodegenerative disorders arise from pathogenic expansions of repeated DNA sequences, summarised in Table 2 [134–137]. The majority of these disorders are characterised by the expansion of trinucleotide repeats (TNR), in particular expanded cytosine-adenine-guanine (CAG) tracts. Amplified CAG triplets are involved in the pathogenesis of Huntington’s disease (HD), several spinocerebellar ataxias (SCAs - SCA1; SCA2; SCA3; SCA6; SCA7; SCA12; SCA17) and spinal and bulbar muscular atrophy (SBMA) [134–136]. In addition to TNRs, expansion of longer nucleotide repeats is present in other neurodegenerative disorders. Expanded hexanucleotide (GGGGCCG4C2) repeats in the intronic region of chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS/ FTD [4,138,139]. HD is an autosomal dominant neurodegenerative disorder that affects 1 in 7300 people in the western population [140]. Amplification of CAG repeats within exon 1 of the huntingtin (HTT) gene results in the expansion of polyglutamine (polyQ) residues in the N-terminus of the huntingtin protein (mtHTT) [141,142]. The presence of mtHTT is toxic to striatal GABAergic neurons, resulting in the degeneration of the striatum. mtHTT misfolds and aggregates, forming toxic intracellular insoluble inclusions [143,144]. The progressive atrophy of several brain regions causes a triad of symptoms characteristic of HD: motor dysfunction (usually manifested as chorea), psychiatric/behavioural and cognitive impairment [140,145,146]. mtHTT has been shown to impair NHEJ by disrupting Ku70-Ku80 heterodimer formation and Ku70-DNA interaction. Consequently, the DNA-PK complex activity was compromised (Fig. 1G). In turn, overexpression of Ku70 was shown to ameliorate the HD phenotype in R6/2 mouse models [147,148]. Similarly, the activity of the homologous recombination (HR) protein, BRCA1 was defective, which was concomitant with impaired γH2AX distribution in HD striatal neurons. This effect was restored by ectopic expression of BRCA1 [149]. Interestingly, the BRCA1 gene was shown to be upregulated in the microglia of ALS patients with SOD1 mutations. BRCA1 activity is crucial during cortical development of the brain. Increased expression of BRCA1 might therefore be neuroprotective in ALS-mutation carriers during early embryonic development [150]. Similar to PD, inhibition of PARP1 was found to be neuroprotective 4

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in R6/2 HD models, which showed increased cell survival and decreased apoptosis [151]. This was caused by an increase in cAMP response element–binding protein (CREB) activity, a transcription factor impaired in HD models [151–153]. Increased CREB activation resulted in upregulation of the neuronal survival factor, brain-derived neurotrophic factor (BDNF) (Fig. 1E) [151]. Moreover, SIRT1-driven deacetylation was shown to decrease PARP1-dependent cell death [154]. SIRT1 is a deacetylase involved in autophagy. Activation of SIRT1 was shown to induce autophagy in HD models, reducing mutant HTT aggregation and toxicity [155]. Dysregulation of FUS has also been associated with HD. Co-aggregates of mutant HTT and FUS were found in brain lysates of HD mouse models. Mutant HTT sequesters FUS, decreasing the pool of functional FUS and worsening HD mouse phenotypes. This induces changes at the transcriptome level which indicates that FUS might act as a genetic modifier in HD [156]. The hexanucleotide repeat expansion in C9orf72 ALS/FTD has also been widely linked to DNA damage [157]. The G4C2 repeats in C9orf72 are prone to form abnormal DNA structures such as G-quadruplexes and DNA:RNA hybrids (R-loops). These structures interfere with the function of RNA polymerases at the repeat sites, resulting in the formation of abortive and decreased full-length transcripts [158]. These abnormalities can be deleterious to the cells, as shown by the increase of DNA damage and apoptotic markers, such as γH2AX and p53 in motor neurons derived from C9orf72 patients [159]. The accumulation of aggregated misfolded proteins due to defects in protein degradation is a pathological hallmark of polynucleotide neurodegenerative diseases [160,161]. In ALS/FTD, accumulation of p62 aggregates is often observed as a consequence of impaired autophagy [4,162,163]. A recent report has described the link between protein degradation malfunction and DNA damage. In ALS/FTD, C9orf72 repeat expansions disturbed ATM-mediated chromosomal-break repair due to accumulation of p62 and defective RNF168-mediated H2A ubiquitination (Fig. 1B) [163]. As p62 accumulates in the nucleus of autophagydeficient cells, it inhibits RNF168, an E3 ubiquitin ligase which signals for the recruitment of downstream NHEJ and HR repair proteins [164,165]. Consequently, C9orf72 neurons exhibited increased unrepaired DSBs due to defective 53BP1 recruitment, which triggered premature cell death and promoted neurodegeneration (Fig. 1B) [163]. The perturbed autophagy is primarily due to the propensity of the G4C2 RNA expansion to undergo repeat-associated non-ATG (RAN) translation, a non-canonical translation mechanism independent of the AUG start codon [157,166]. Consequently, the G4C2 transcript can be translated bidirectionally from all its reading frames, producing dipeptide repeat (DPR) proteins: poly-glycine-alanine (GA), poly-glycineproline (GP), poly-glycine-arginine (GR), poly-proline-alanine (PA) and poly-proline-arginine (PR) [157,166,167]. Accumulation of DPRs and p62 has been detected in the brain and spinal cord of ALS/FTD patients [167,168]. A recent report has highlighted the possibility of detecting poly-GP in the CSF of ALS/FTD patients [169]. Poly-GP is one of the most frequent DPRs observed in C9orf72 ALS/FTD patients and is present in the pre-symptomatic phase. Therefore, DPRs can be recognised as promising biomarkers for early diagnosis, thus facilitating the identification of other DPRs implicated in different neurodegenerative disorders [170,171]. A recent study showed a weak association between C9orf72 repeat length measured in lymphocytes of pre-symptomatic carriers and the age of clinical onset. The correlation between repeat length and age of onset was affected by the age at sample collection. This suggests that measuring C9orf72 expansions from blood samples is not a reliable biomarker to predict the age of onset or the clinical features in C9orf72 expansion carriers [172]. C9orf72 repeat length has been investigated by several researchers, however, due to the conflicting results reported, no clear-cut conclusions can be made, as reviewed by Mossevelde et al. [137].

6. Ruijs-Aalfs syndrome Ruijs-Aalfs syndrome (RJALS) is a rare autosomal recessive premature ageing disorder [173–175]. Common characteristics of the disease include: progeroid features, early development of hepatocellular carcinoma and chromosomal instability [174,176]. RJALS arises due to mutations in SPRTN which encodes the DNA dependent metalloprotease Spartan, also known as DNA damage-targeting VCP (p97) adaptor C1orf124 (DVC1) [177,178]. Spartan consists of an N-terminal SprT metalloprotease domain, a p97/VCP-binding motif (SHP), a PCNA-interacting peptide (PIP) and a ubiquitin binding zinc-finger domain (UBZ) [179]. Mutations that result in RJALS either lead to the expression of a truncated protein, resulting in loss of the SHP, PIP and UBZ domains, or reduction of the metalloprotease activity [174]. Spartan is intimately involved in the repair of protein-linked DNA breaks (PDBs), as reviewed by Stingele et al. [180]. p97/VCP is a highly conserved AAA+-type ATPase that functions as a part of the ubiquitin-proteasome system [181]. The interaction between p97 and Spartan was identified by immunoprecipitation and mass spectrometry under control and DNA damage conditions [177,182]. The interaction between p97 and Spartan has been suggested to promote the dissociation of DNA polymerase η following translesion synthesis (TLS) in order to minimise the introduction of mutations into the genome [177]. In addition, it has been shown that Spartan recruits p97 to stalled DNA replication forks and sites of DNA damage [177]. Mutations or changes in p97 expression have been found to be associated with neurodegeneration and premature ageing due to its important role in protein disposal [183,184]. Ramadan et al. proposed that the premature ageing phenotype observed in RJALS patients is due to the disruption of the normal interaction between Spartan and p97 [185]. They also suggested that this may be the case in Werner syndrome, as p97 interacts with the WRN helicase in the nucleoli following DNA replication stress [185]. Although no neurodegenerative phenotypes in RJALS patients have been described in published literature, the role of Spartan in PDB repair suggests that SPRTN mutations would lead to a disease similar to spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) which is caused by the defective tyrosyl-DNA phosphodiesterase 1 (TDP1), another PDB repair factor [186–189]. A plausible explanation could be that these patients may have not yet had the opportunity to develop a neurodegenerative phenotype due to their young age. Two of the three documented cases of RJALS have resulted in death by the age of 18 due to complications with hepatocellular carcinoma [174]. 7. Emerging tools for the detection of neurological diseases Recent advances in the field of material science and analytical technologies have led to the rapid development of biosensors. They harness the unique optical and electrochemical properties of materials such as carbon nanotubes (CNTs), gold nanoparticles (AuNPs) and quantum dots (QDs). Ganesh et al. have recently reviewed the developed biosensors for the detection of DNA, miRNA and proteins associated with neurodegenerative disorders, such as AD, PD and prion diseases [190]. The DNA repair players implicated in neurodegenerative disorders, topoisomerase 1 (TOP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2) have been detected and quantified using the gold aggregating gold (GAG) assay [191]. The unique optical and physicochemical properties of gold and magnetic nanoparticles are employed to detect and quantify the mRNA transcripts. Another recent tool that is expected to revolutionise the protein detection technologies is the use of aptamers. Aptamers are the oligonucleotide equivalents of antibodies. Their increased stability, in vitro selection and minimal variability across different batches make their incorporation into the diagnostics field very promising. McKeague extensively reviewed different aptamers for the detection of DNA damage adducts, repair proteins and mutated gene products [192]. Their low 5

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abundance in genomic samples makes it challenging to incorporate in the field of diagnostics. Hence, developing highly sensitive and specific technologies for detection is essential. Aptamers have been incorporated in various colorimetric, lateral flow, electrochemical, electro-chemiluminescent and fluorescence-based assays. These include gold nanoparticle- and magnetic bead-based assays in addition to multiplex platforms, thus facilitating the potential use of aptamers in point-of-care diagnostics [193].

capacity [210]. In contrast, proliferation and mitosis in mutant top2b embryos is not affected [231]. Instead, they show a marked phenotype in their post-mitotic cells in the retina and optic tectum. Similarly, Top2b-/- mice also have a defect in their post-mitotic cells [242–244]. Recently, an in vivo system was developed to visualise TDP-43 mislocalisation at a single-cell level in the zebrafish spinal cord [213]. By inducing a transgenic model expressing GFP-tagged human TDP-43 with UV damage, they were able to observe neurodegeneration, closely resembling the pathology present in humans. In addition, they showed that correct TDP-43 localisation is microglia-dependent. Although the tardbp knockout zebrafish, generated by another group, do not have a phenotype, additional knockout of TAR DNA binding protein-like (tardbpl) leads to muscle degeneration, impaired spinal motor neuron outgrowth, strongly reduced circulation, mispatterning of blood vessels and early death [214]. In contrast, Tardbp knockout mice are embryonic lethal, impeding loss-of-function studies in this model [245]. Zebrafish have β- and γ-synucleins, but lack α-synuclein, facilitating investigations using human α-synuclein [246]. Expression of wild-type α-synuclein in neurons causes early embryonic lethality, while its expression in peripheral sensory neurons leads to axonal dystrophy and death of 20% of cells by 3 days post-fertilisation [236,237]. Interestingly, while the morpholino (MO) knockdown of both β- and γ-synucleins leads to impaired development of the dopaminergic system, this phenotype is rescued by the overexpression of human α-synuclein [247]. Although many genetic models associated with both neurological disease and DNA repair have been generated in zebrafish, the connection between the two has not been extensively investigated in this organism. In addition, many important models are yet to be developed using CRISPR, such as atm, tdp1, top1 and rnaseh2a. Future exploration of progressive neurological decline in a mature ageing zebrafish, as well as the embryo, is crucial in order to better understand the underpinning disease mechanisms. This knowledge can in turn be used to discover new disease-modifying treatments with the help of state-of-the-art techniques like in vivo imaging and chemical screening.

8. Prospective model organisms Numerous mouse models of DNA repair and neurodegeneration have been generated and reviewed to date [5]. We would therefore like to discuss a relative newcomer in the field - the zebrafish. Zebrafish are becoming increasingly popular as a model organism as they possess many advantages over traditional vertebrate models, such as short generation times, high fecundity, larval transparency and lower cost, whilst still maintaining high similarity with the human genome. Although there are some limitations, such as the lack of zebrafish antibodies, this is outweighed by the availability of high-throughput methods. In addition, zebrafish knockouts for multiple genes can easily be generated in a relatively short time-frame. With the advent of CRISPR/Cas9 technology, generation of knock-ins will also soon become a routine technique [194–198]. Zebrafish has orthologues of genes involved in all known human DNA repair pathways and its nervous system, whilst exhibiting some differences, has similar gross organisation to that of humans and all the major neurotransmitter pathways [199–201]. Most zebrafish DNA repair studies explore the role of DNA repair in embryonic development and how it is affected by various toxins, some of which have been reviewed by Pei and Straus, and it has also been extensively used for modelling cancer and neurodegeneration [202–204]. However, several studies have indeed investigated DNA repair factors linked to neurodegeneration, such as Tdp2, Tdp-43, Atm, and neurological disease-associated factors that activate DDR pathways, such as topoisomerase 2α (Top2a), topoisomerase 2β (Top2b), Fus, α-synuclein, C9orf72 and Sod1 (Table 3) [205–217]. TDP2 (previously known as TTRAP and EAP2) is an enzyme that resolves double-stranded topoisomerase 2 cleavage complexes (Top2cc) [231]. Mutations in TDP2 cause spinocerebellar ataxia, autosomal recessive 23 (SCAR23), which manifests in intellectual disability, seizures and ataxia [219,220]. However, it has proven difficult to study since yeast do not have a TDP2 orthologue and attempts to crystalize fulllength human TDP2 have failed due to insufficient solubility. The crystal structure of zebrafish Tdp2 was therefore determined due to its higher solubility and amenability to crystallization [205,238]. Zebrafish Tdp2 active site and DNA-binding sites have been humanised by amino acid substitution for crystal structure studies with inhibitors, which has led to the development of a TDP2 inhibitor discovery platform [240]. In addition, it has been shown that tdp2 knockdown in early zebrafish embryos interferes with gastrulation due to its role in cell migration [229]. The role of topoisomerases in regulating proliferation is crucial during the development of the nervous system, whilst in the mature organism these enzymes are required for transcription (reviewed in [241]). TOP2A and TOP2B carry out overlapping functions, however, TOP2A is essential for proliferation and TOP2B is required for transcription. Top2a mutations in zebrafish are embryonic lethal, like yeast and mouse mutants, however unlike mouse, zebrafish embryos survive into the larval stages due to the presence of maternal top2a mRNA [206,210,230]. All three top2a−/− mutants (hi3635, can4 and blm) exhibit small eyes and brain, brain necrosis and body curvature. While cell cycle defects were not investigated in the hi3635 mutant, can4 and blm were shown to have altered phospho-histone H3 staining and accumulation of cells in G2/M [206,210]. Furthermore, adult hi3635-/+ and can4-/+ fish have a significant reduction in their liver regeneration

9. Conclusions and perspective It is undoubtedly true that next generation sequencing has revolutionised the molecular diagnostics field [248]. While the identification of genetic biomarkers may be specific for certain populations, they do constitute an important tool for researchers to investigate underlying mechanisms that cause neurological disorders. On the other hand, biochemical biomarkers would be more helpful for diagnosing and monitoring disease progression in patients [249]. Molecular biomarkers for some disorders have been identified and utilised in the clinic, for instance, Aβ for AD. However, they fail to reflect or encompass the entire disease repertoire and do not aid complete preclinical detection, diagnosis and monitoring of disease progression. This leads to the requirement of using several biomarkers simultaneously [88]. Most neurological disorders are multi-factorial with overlapping symptoms. As a result, biosensors capable of multiplexed detection of several biomarkers would prove to be a crucial mean for the early detection and diagnosis [190]. Investigating DNA damage as part of routine diagnosis of neurological disorders provides further insight into the DNA repair dysregulation in patients and paves the way for more efficient intervention and personalised therapy. Identification and utilisation of potential biomarkers requires understanding of the pathological molecular mechanisms at play, which would be impossible without appropriate model organisms. Mouse studies have been invaluable in furthering our understanding, however, in vivo investigations are difficult, and generation of knockouts is lengthy, often resulting in embryonic lethality. With the advent of cutting-edge genetic editing and in vivo imaging technologies, the zebrafish is becoming an indispensable tool in the study of DDR pathways and associated neurological disease. 6

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Table 3 A selection of zebrafish models of DNA repair and neurological diseases. MO – morpholino, tg – transgene, PC – Purkinje cell, dpf – days post fertilisation, hpf – hours post fertilisation. Disease

Zebrafish models

Phenotype

ALS/FTD

C9orf72 MO C9orf72−/− C9orf72 HRE C9orf72-ATG-poly-GA C9orf72-ATG HRE

Strongly reduced mobility, axonal growth defect [221] No phenotype [222] Mild cardiac phenotype [223] Inclusions in the muscle, circulation defect at 2 dpf and severe pericardial oedema at 4 dpf, early death [223] Accumulation of RNA foci and DPRs, motor deficits, cognitive impairment, motor neuron loss, muscle atrophy and death in early adulthood [207] Axonopathy [224,225]

SOD1MT, transient expression tg(SOD1G93A) tg(SOD1G93R) SOD1T70I tardbp−/− tardbp−/−; tardbpl−/− fus−/− fus MO

Loss of neuromuscular junctions, motor neuron innervation changes, motor dysfunction and decreased activity [224] Neuromuscular junction alterations in larvae and adulthood, decreased endurance in the swim tunnel test in adults; motor neuron loss, muscle atrophy, paralysis and death at end stage [209] Early neuromuscular junction phenotype, susceptibility to oxidative stress, late-onset motor neuron disease phenotype [226] No phenotype, compensation from tardbpl [214] Muscle degeneration, impaired spinal motor neuron outgrowth, reduced circulation, blood vessel mis-patterning and early death [214] No phenotype, mild changes in brain transcriptome and proteome [216] Motor neuron degeneration, swimming defects [227]

AT SCA13

atm MO SCA13R420H, PC-specific expression

AT-like radiosensitivity with developmental abnormalities and death by 72 hpf [211] Progressive PC degeneration, eye movement defects and behavioural phenotypes [228]

SCAR23

tdp2 (ttrap) MO blm (top2a−/−) can4 (top2a−/−) hi3635 (top2a−/−)

Perturbed gastrulation [229] Altered pH3 staining, cell Larvae with small eyes and brain, brain necrosis, accumulation in G2/M [206,210] tail curvature, death at 4 – 5 dpf [206,210,230] Pericardial oedema and progressive wasting at 3 – 5 dpf [206,230] Brain necrosis and tail curvature at 24 hpf, small number of bridged nuclei [210] Defects in retina and optic tectum [231]

top2a MO top2b−/−

Significantly reduced liver regeneration capacity in heterozygous adults [210]

HD

mHTT-ΔN17-exon1 mHTT-exon1 HTT-polyQ overexpression mHTT-exon1, retinal expression

Rapidly progressing movement deficit [232] Delayed-onset movement deficits, slow progression [232] Inclusions, embryonic developmental delay, abnormalities, apoptosis and decreased viability [233,234] Specific cellular degeneration, protein aggregation in the rod layer of the retina [235]

PD

α-syn expression in neurons tg(α-syn) in sensory neurons

α-syn aggregates, death at 10 dpf [236] α-syn aggregates, most α-syn expressing cells dystrophic, 20 % die by 3 dpf [237]

Declaration of Competing Interest No conflict of interest declared. Acknowledgements The authors would like to thank members of the El-Khamisy lab for useful discussions. This work is supported by a Wellcome Trust Investigator Award (103844) and a Lister Institute of Preventative Medicine Fellowship (137661) to S.F.E-K. R.Z is additionally funded by a Rosetrees Trust grant. References [1] D. Stein, D. Toiber, DNA damage and neurodegeneration: the unusual suspect, Neural Regen. Res. 12 (2017) 1441, https://doi.org/10.4103/1673-5374.215254. [2] P.J. McKinnon, DNA repair deficiency and neurological disease, Nat. Rev. Neurosci. 10 (2009) 100–112, https://doi.org/10.1038/nrn2559. [3] S.F. El-Khamisy, To live or to die: a matter of processing damaged DNA termini in neuronsl, EMBO Mol. Med. 3 (2011) 78–88, https://doi.org/10.1002/emmm. 201000114. [4] C. Walker, S.F. El-Khamisy, Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia, Brain 141 (2018) 1247–1262, https://doi.org/10.1093/brain/awy076. [5] R. Madabhushi, L. Pan, L.H. Tsai, DNA damage and its links to neurodegeneration, Neuron 83 (2014) 266–282, https://doi.org/10.1016/j.neuron.2014.06.034. [6] M. O’Driscoll, Diseases associated with defective responses to DNA damage, Cold Spring Harb. Perspect. Biol. 4 (2012) 1–26, https://doi.org/10.1101/cshperspect. a012773. [7] A. Ciccia, S.J. Elledge, The DNA damage response: making it safe to play with knives, Mol. Cell 40 (2010) 179–204, https://doi.org/10.1016/j.molcel.2010.09. 019. [8] K. Ramadan, S. Halder, K. Wiseman, B. Vaz, G. Ghosal, J.W.-C. Leung, B.C. Nair,

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