Crosstalk Between Different DNA Repair Pathways Contributes To Neurodegenerative Diseases Part 2

3.2. Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of the population over 60 years of age worldwide. The disease is characterized by asymmetrical bradykinesia, rigidity, resting tremor, and postural instability. 

Parkinson's disease is a common neurological disease that is characterized by movement disorders and tremors. However, as the disease progresses, patients' cognitive abilities and memory can also be affected. Although these problems may make life more difficult for patients, a positive attitude and proper treatment can alleviate the condition and improve the quality of life of patients.

Although Parkinson's disease affects patients' memory and learning ability, it does not mean that they cannot maintain and improve their memory. Studies have shown that people with Parkinson's disease can improve their memory by using some helpful techniques and methods.

For example, patients can improve their memory through deliberate training. This includes keeping a regular schedule, doing memory training, and communicating with others to increase social networks. In addition, patients can also use some memory aids such as calendars, memos, or alarm clocks to help them remember important things.

In addition to these methods, some healthy lifestyle habits can help patients improve their cognitive abilities and memory. For example, getting enough sleep, eating a healthy diet, exercising moderately, and avoiding excessive use of electronic devices.

Most importantly, people with Parkinson's disease must maintain an optimistic attitude. They should seek help and support, including family, friends, and medical professionals. With a positive attitude and the right approach, people with Parkinson's can continue to stay positive and live a more fulfilling life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory responses in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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The cardinal pathologic features of PD include the progressive loss of dopaminergic neurons in the pars compacta of substantia nigra (SN), α-synuclein (α-SYN) aggregation, and Lewy body formation in the mid-brain region. Like AD, PD is a multifactorial disease caused by both environmental and genetic factors. Familial PD is associated with mutations in LRRK2, PARK7, PINK1, or SNCA [81,82]. 

Since oxidative stress and mitochondrial dysfunction are prominent features in PD, there has been a focus on studying the neuroprotective properties of mitochondrial DNA repair. 

Indeed, recent genetic data suggested that, on a pathway level, variants in genes involved in mtDNA maintenance may be enriched in PD patients [83]. The role of nuclear DNA repair is less well established, but elevated levels of 8-oxoG, SSBs, and DSBs have been found in both PD post-mortem human brains and in rat PD models [84–86]. 

Mice heterozygous for a deletion in the NER gene Ercc1, which only functions in nuclear DNA repair, had increased levels of phosphorylated α-SYN, γH2AX foci in the striatum, and developed severe PD-like pathology following MPTP administration [87]. 

These findings support that the nuclear DNA repair machinery plays a role in PD pathology, but the mechanisms involved remain elusive. The BER DNA glycosylases OGG1, MTH,1, and MUTY1 are highly expressed in SN and associated dopaminergic neurons in PD brains [88–90]. Consistently, Ogg1 knock-out mice showed behavioral defects and elevated 8-oxoG levels [90,91]. 

A direct, functional coupling between PD susceptibility genes and BER is suggested from the observation that Parkin ubiquitinates Apurinic/apyrimidinic endonuclease 1 (APE1) under stress. Moreover, mutations in PRKN abrogate APE1 ubiquitination, resulting in the overactivation of APE1 and resulting inSSBs formation [92]. Elevated levels of AP sites were found in mtDNA in nigra l dopaminergic neurons from PD patients [93]. 

Polymorphisms in APE1 and OGG1 have been suggested to increase the risk of PD [94,95], but no individual single nucleotide polymorphism (SNP) in BER genes is consistently found to be associated with PD risk across cohorts [96,97]. 

However, elevated levels of pathological α-SYN correlated with increased PARP1 levels and PARylation in the brain and cerebrospinal fluid of PD patients, supporting the activation of cellular responses to SSBs. 

Interestingly, nuclear α-SYN may bind DNA and DDR proteins [98], and increased PARylation has been shown to promote pathological α-SYN aggregates [99]. 

Taken together, evidence of a direct functional coupling between DDR and α-SYN is emerging, suggesting a potential role for nuclear DDR in proteotoxicity in PD.

3.3. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative motor neuron disease, affecting the motor cortex, brain stem, and spinal cord, leading to progressive paralysis and eventually death [100]. 

ALS is considered, primarily, a sporadic disease, but about 10% of ALS cases are familial [101]. More than 40 genes are currently linked to ALS, and the majority of cases, both familial (fALS) and sporadic ALS (sALS), are caused by mutations in four genes: C9ORF72, SOD1, TARDBP and FUS/TLS [102,103]. 

Over 30 years ago, a hypothesis suggesting the accumulation of abnormal DNA as the primary abnormality in ALS was brought forward [104]. This has later been substantiated by many studies showing AP sites, DNA SSBs, and 8-oxoG accumulation in diseased human motor neurons [105,106], further supporting that defective DDR is involved in ALS. 

Defects in SOD1, the first identified ALS gene, which acts as a scavenger against free radicals, link oxidative damage with ALS [107]. The activation of several key proteins that function in sensing DNA damage, e.g., ATM, has been shown in human ALS motor neurons with SOD1 mutations, suggesting DNA damage accumulation in SOD1 deficient neurons [105]. 

Whole exome sequencing revealed NIMA-related kinase 1 (NEK1) as another ALS-associated gene. NEK1 functions in cell-cycle checkpoint control [108] and contributes to DDR independent of ATM and ATR [109]. Human induced pluripotent stem cells (iPSCs) and differentiated motor neurons carrying NEK1 mutations show dysregulation of the DDR machinery and increased DNA damage [110]. 

APE1 and OGG1 are upregulated in ALS brains [111] and spinal cord motor neurons in SOD1 transgenic mice, respectively, indicating increased DNA oxidative base damage [112]. 

Hypomethylation of the APE1 and OGG1 promoter regions has recently been described in ALS [105]. The authors speculated that hypomethylation might represent a compensatory upregulation of these BER genes in the vulnerable ALS neurons to cope with oxidative stress. Interestingly, two RNA/DNA binding proteins encoded by ALS pathogenic genes, TARDBP and FUS/TLS, function in DNA damage response. 

Mitra et al. showed DSB accumulation and reduced recruitment of the XRCC4-XLFDNA ligase 4 (LIG4) complex at DSB sites, thus indicating attenuated NHEJ in TDP-43 (encoded by TARDBP) depleted motor neurons. 

Moreover, the authors demonstrated that TDP-43 acts as a scaffold, facilitating the recruitment of the XRCC4/LIG4 complex to DSBs [113]. Recent studies revealed that FUS is recruited to DSBs and interacts directly with PARP1 [114,115]. 

Moreover, the interaction between FUS and Histone deacetylase 1 (HDAC1) promotes NHEJ [116,117]. A non-canonical translation mechanism leads to the production of five dipeptide repeat proteins (DPRs) from the hexanucleotide repeat expanded C9ORF72 gene. 

A recent study indicated that, among the five DPRs, proline arginine (PR), glycine-arginine (GR), and glycine-alanine (GA) are the most neurotoxic and decrease the efficiency of NHEJ, single-strand annealing and microhomology-mediated end joining (MMEJ) [118]. 

Consistently, increased levels of several DDR markers (γH2AX, phosphorylated ATM, cleaved PARP1, and 53BP1) were observed in spinal cord motor neurons of C9ORF72 ALS patients [119]. 

Taken together, these studies suggest that several DNA repair pathways are implicated in NDD pathogenesis; however, the exact molecular mechanisms by which the responses to genomic stress contribute to neurodegeneration are still unclear. 

4. Crosstalk between DDR and Age-Related Neurodegenerative Diseases

From the above, it is clear that impaired DDR may contribute directly or indirectly towards various NDDs. Moreover, individual DDR proteins may be involved in more than one NDD (Figure 2). Dysregulation, dysfunction, or inactivation of ATM is reported in AD and PD. 

Using a fly model, Petersen et al. showed that even a slight reduction in ATM kinase activity caused neurodegenerative features [120]. Reduced ATM levels and activity have been shown in hippocampal and frontal cortex neurons in AD brains as well as in AD transgenic mice [72]. 

The dysregulation of ATM signaling was also reported in HD where, contrary to AD or AT, increased or persistent activation of ATM signaling correlated with disease progression [121,122]. 

In a rodent PD model, α-synucleinopathy led to the upregulation of γH2AX, 53BP1, and the phosphorylation of ATM in neurons [87,123], suggesting that DSB might contribute to DA neurodegeneration in aging brains. 

The DSB repair protein BRCA1 affected cognitive function in transgenic human amyloid precursor protein (hAPP) AD mice, where small-hairpin RNA-mediated knockdown was accompanied by a reduction in memory and learning ability [73]. 

In post-mortem AD brains, hypomethylation of the BRCA1 promoter region was accompanied by the upregulation of expression and cytosolic mislocalization of BRCA1 [124]. 

In AD, the expression of BRCA1 was increased, possibly as a consequence of oxidative DNA damage accumulating due to Aβ-induced ROS formation [125]. However, in this case, the upregulation of BRCA1 did not translate to increased DDR capacity because BRCA1 remained dysfunctional and co-aggregated with TAU in a highly insoluble form, making it unavailable for DNA repair [124,126–128]. 

Hence, increased expression does not always lead to increased repair capacity, but it is suggested that BRCA1 can function by a dual mechanism in AD: while it can cause abnormal ubiquitination and sub-cellular distribution of presenilin 1 (PS1) and thereby affect Aβ processing, it can also induce pro-apoptotic signaling [128]. 

Hence, also in AD, the emerging evidence suggests a direct functional coupling between DDR and central pathogenic components. Whether this is also the case in ALS remains to be determined, but transcriptomic profiling shows that BRCA1 is highly expressed in the microglia of human ALS patients [129]. 

Mice that are deficient in the NHEJ repair enzymes LIG4 and XRCC4 along with Ku70 and Ku80 show apoptosis of post-mitotic neurons [130]. 

Abnormal expression of DNA-PK has been reported in AD. Reduced NHEJ activity in cortical neurons and cortical extracts from AD brains was ascribed to lower protein levels of DNA-PK and its regulatory subunit Ku80 [131,132]. Aβ aggregates inhibit DNA-PK activity in nerve growth factor differentiated PC12 cells by reducing the expression of DNA-PKcs in a ROS-dependent manner [133]. 

Aβ can enter the nucleus of PC12 cells and downregulate the expression of DNA-PKcs through a mechanism independent of oxidative stress, thus indicating that Aβ itself may attenuate DNA-PKcs activity and hence reduce NHEJ capacity. 

As mentioned above, DNA-PK deficiency also leads to SMA [55]. PARP1 is activated by SSB to synthesize poly-ADP ribose (PAR) polymers at the damaged site [134–139]. 

Constitutive PARP1 activation can deplete intracellular NAD+ levels, which can affect mitochondrial homeostasis, ROS production, DNA repair, and cell death [140–142]. A correlation between PARP1 activation and AD has been shown in AD human brains and AD mouse models [143–146]. Additionally, it has been shown that MPTP-treated mice exhibit PARP1 activation [147]. 

A mechanistic link between PARP1 activation and neurodegeneration was supported by Parp1−/− mice being resistant to the toxic effects of MPTP [147]. In ALS patients, PARP1-mediated, caspase-independent programmed cell death of motor neurons through parthanatos was reported in the spinal cord [148–150]. Thus, PARP1 emerges as one of the central DDR proteins involved in most of the NDDs (Figure 2). 

The available evidence suggests that PARP1-mediated AD and PD pathologies could result from several cellular pathways: (i) bioenergetic deficit via NAD+ depletion; (ii) the activation of apoptosis via interaction with tumor suppressor and apoptotic genes such as TP53 and BCL2; (iii) the induction of parthanatos; and (iv) transcription rewiring via the modulation of transcriptional factors [145]. 

A causal role for PARP1 activation in NDD pathogenesis is further substantiated by studies where PARP1 inhibition and NAD+ -augmentation prevented neuron degeneration in PD animal models [99,151]. Based on this, Nicotinamide riboside supplementation was proposed as a possible therapeutic intervention for NDDs [151].

5. Crosstalk between DDR and Other Cellular Processes Known to Be Disturbed in NDDs

From the above, it is apparent that defects in DNA repair proteins may contribute towards the initiation and progression of more than one NDD. In this section, we will describe some of the unifying mechanisms observed in various NDDs and will provide evidence for their crosstalk with the DDR machinery (Figure 3).

Figure 3. Crosstalk between different cellular mechanisms involved in various NDDs. The figure represents crosstalk between DDR and other cellular processes known to be perturbed in various NDDs. Created by Ellen Tenstad @ScienceShaped.

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