**4. The interactions between oxidative damage in the striatum, sex, life span, and the age of onset of diseases in neurodegenerative patients**

Many neurological diseases show significant sex differences in their susceptibility, severity, and progression [35, 36]. Specifically, a male bias has been found for disorders such as PD and attention-deficit hyperactivity disorder (ADHD), both of which are associated with abnormal levels of dopamine [37–39]. Considerable studies have supported the hypothesis that gonadal sex steroid hormones, especially estrogen, act as protectors in females by modulating dopamine release, metabolism, and dopamine receptors' activity. However, there is numerous evidence that genetic factors, especially sex-specific genes, influence either healthy or diseased dopamine systems [40–42].

As shown in **Figure 4**, Kendall's tau\_b analysis revealed a significant positive correlation between sex and 8-oxo-dG levels in the caudate of PD cases. The result indicates that there is a sex difference concerning DNA damage in late-stage PD patients. Postmortem brain studies have revealed that the expression of PD-related genes in the substantia nigra pars compact (SNc), such as α*-synuclein* and *PINK-1*, is higher in men than women [43]. Sex-chromosome genes are critically involved, particularly the sex-determining region of the Y chromosome (*SRY*) gene [44]. The dopaminergic toxin, 6-hydroxydopamine (6-OHDA), has been described to significantly elevate *SRY* mRNA expression in human male dopamine cells, accompanied by an increase in the expression of GADD45γ, a DNA damage-inducible factor gene and a known *SRY* regulator. Interestingly, SRY upregulation initiated by dopamine cell damage is a protective response in males; however, the effect diminishes significantly with the gradual loss in dopamine cells [19].

DNA damage may be unique in its ability to promote multiple symptoms associated with old age. Exposure of rodents to ionizing radiation leads to the premature

**Figure 4.**

*Kendall's tau\_b analysis of the correlation between sex and 8-oxo-dG levels in the caudate from PD brains (p = 0.020).*

appearance of numerous histological features of healthy aging—gray hair, kidney disease, cataracts, osteoporosis, neuronal atrophy, and muscle atrophy. A classic mouse species survive a maximum life span of 2–4 years, whereas humans can live up to 122 years [45]. Body mass can account for approximately 60% of the mammalian life span variance, while another 40% is attributed to other factors. The mitochondrial electron transport chain yields superoxide, a reactive form of oxygen, which can damage proteins, lipids, and DNA. Superoxide generates immediately into hydrogen peroxide, promoting several forms of oxidative damage. Animals engineered to have reduced rates of oxidative lesions, make efforts to exhibit average life spans [46], which provides insights into the significant negative correlation between life span and 8-oxo-dG levels in the putamen of healthy aging groups (**Figure 5**). It seems conceivable that transcription-associated DNA damage is critically involved in the aging process of mammals.

The reverse is precisely the PDD cases, as shown in **Figure 6**, there is a significantly positive correlation between life span and 8-oxo-dG levels in the caudate of PDD patients. The result supporting a role for ROS in regulating the rate of aging was characterized as "at best equivocal" in a published comprehensive review of aging in the mouse [47], which can be explained as ROS increases life span by stimulating protective stress responses [48].

On the other side, quite a few repair enzymes recognize and remove many types of DNA damage from the genome, and failure of these mechanisms can lead to the accumulation of damage in the neurodegenerative diseases. Failure to repair DNA, in reverse, may cause the synthesis of defective proteins, which definitely will repair DNA less efficiently [49].

Genome-wide association studies (GWAS) of Huntington's disease (HD) have focused on genes associated with DNA damage repair mechanisms as modifiers of age at onset, defining an age-related mechanism shared in other hypotheses of neurodegeneration. Many ages at onset in neurodegenerative diseases are clarified to be caused by mutations in bona fide DNA repair factors—tyrosyl DNA-phosphodiesterase 1 (TDP1), aprataxin (APTX), and polynucleotide kinase/ phosphatase (PNKP) [50]. Getting the picture of DNA repair defects in neurodegenerative diseases will shed light on why they affect the age at onset and the disease severity in HD.

#### **Figure 5.**

*Correlation between life span and 8-oxo-dG concentration in the putamen from the control brains (rs = −0.650, p = 0.042). Rs, the Spearman's rank correlation coefficient.*

**215**

**Figure 6.**

**Figure 7.**

*The Striatal DNA Damage and Neurodegenerations DOI: http://dx.doi.org/10.5772/intechopen.93706*

*p = 0.041). Rs, the Spearman's rank correlation coefficient.*

*p = 0.010). rs, the Spearman's rank correlation coefficient.*

An exomic sequencing study in a rare age-related ataxia oculomotor apraxia (AOA) identified mutations in the DNA repair scaffold gene *XRCC1*, the knock-out of *XRRCC1* resulted in hyper-PARlation, and genetic ablation of PARP1 prevent disease onset in an AOA-XRCC1 mouse model [51]. N6-furfuryladenine (N6FFA or kinetin)—a natural human metabolite of the DNA repairing ROS damaged adenosine—was protective against neurodegeneration in HD and PD models. The discovery of N6FFA efficacy in HD and PD models indicates a critical signaling pathway between DNA damage and mitochondria, where messed branches of this pathway may lead to different diseases in the brain, with similarities of late age onset [52]. As shown in **Figure 7**, the significantly positive correlation between age at onset and 8-oxo-dG levels in the caudate of the DLB patients, probably indicating that the DNA repair pathway, as genetic modifiers, determines the age at onset. 8-oxo-dG mainly promotes the transversion from GC to TA, GC to AT, or GC to CG, and this

*Correlation between age at onset and 8-oxo-dG concentration in the caudate from the DLB brains (rs = 0.800,* 

*Correlation between life span and 8-oxo-dG concentration in the caudate from the PDD brains (rs = 0.775,* 

*The Striatal DNA Damage and Neurodegenerations DOI: http://dx.doi.org/10.5772/intechopen.93706*

#### **Figure 6.**

*DNA - Damages and Repair Mechanisms*

is critically involved in the aging process of mammals.

stimulating protective stress responses [48].

*p = 0.042). Rs, the Spearman's rank correlation coefficient.*

DNA less efficiently [49].

disease severity in HD.

appearance of numerous histological features of healthy aging—gray hair, kidney disease, cataracts, osteoporosis, neuronal atrophy, and muscle atrophy. A classic mouse species survive a maximum life span of 2–4 years, whereas humans can live up to 122 years [45]. Body mass can account for approximately 60% of the mammalian life span variance, while another 40% is attributed to other factors. The mitochondrial electron transport chain yields superoxide, a reactive form of oxygen, which can damage proteins, lipids, and DNA. Superoxide generates immediately into hydrogen peroxide, promoting several forms of oxidative damage. Animals engineered to have reduced rates of oxidative lesions, make efforts to exhibit average life spans [46], which provides insights into the significant negative correlation between life span and 8-oxo-dG levels in the putamen of healthy aging groups (**Figure 5**). It seems conceivable that transcription-associated DNA damage

The reverse is precisely the PDD cases, as shown in **Figure 6**, there is a significantly positive correlation between life span and 8-oxo-dG levels in the caudate of PDD patients. The result supporting a role for ROS in regulating the rate of aging was characterized as "at best equivocal" in a published comprehensive review of aging in the mouse [47], which can be explained as ROS increases life span by

On the other side, quite a few repair enzymes recognize and remove many types of DNA damage from the genome, and failure of these mechanisms can lead to the accumulation of damage in the neurodegenerative diseases. Failure to repair DNA, in reverse, may cause the synthesis of defective proteins, which definitely will repair

Genome-wide association studies (GWAS) of Huntington's disease (HD) have focused on genes associated with DNA damage repair mechanisms as modifiers of age at onset, defining an age-related mechanism shared in other hypotheses of neurodegeneration. Many ages at onset in neurodegenerative diseases are clarified to be caused by mutations in bona fide DNA repair factors—tyrosyl DNA-phosphodiesterase 1 (TDP1), aprataxin (APTX), and polynucleotide kinase/ phosphatase (PNKP) [50]. Getting the picture of DNA repair defects in neurodegenerative diseases will shed light on why they affect the age at onset and the

*Correlation between life span and 8-oxo-dG concentration in the putamen from the control brains (rs = −0.650,* 

**214**

**Figure 5.**

*Correlation between life span and 8-oxo-dG concentration in the caudate from the PDD brains (rs = 0.775, p = 0.041). Rs, the Spearman's rank correlation coefficient.*

#### **Figure 7.**

*Correlation between age at onset and 8-oxo-dG concentration in the caudate from the DLB brains (rs = 0.800, p = 0.010). rs, the Spearman's rank correlation coefficient.*

An exomic sequencing study in a rare age-related ataxia oculomotor apraxia (AOA) identified mutations in the DNA repair scaffold gene *XRCC1*, the knock-out of *XRRCC1* resulted in hyper-PARlation, and genetic ablation of PARP1 prevent disease onset in an AOA-XRCC1 mouse model [51]. N6-furfuryladenine (N6FFA or kinetin)—a natural human metabolite of the DNA repairing ROS damaged adenosine—was protective against neurodegeneration in HD and PD models. The discovery of N6FFA efficacy in HD and PD models indicates a critical signaling pathway between DNA damage and mitochondria, where messed branches of this pathway may lead to different diseases in the brain, with similarities of late age onset [52]. As shown in **Figure 7**, the significantly positive correlation between age at onset and 8-oxo-dG levels in the caudate of the DLB patients, probably indicating that the DNA repair pathway, as genetic modifiers, determines the age at onset. 8-oxo-dG mainly promotes the transversion from GC to TA, GC to AT, or GC to CG, and this

is an important mechanism of ROS-induced mutation [53]. The study examined the DNA-repair capacities of basal cell carcinoma (BCC) skin cancer patients and revealed that the age at the first onset of BCC positively correlated with DNA repair, suggesting that the earlier the age of onset, the lower was their DNA repair [54].
