**5. Role of oxidative stress in pathogenesis of Huntington's disease (HD)**

Huntington's Disease, a neurological disorder is associated with unstable amplification of cytosine, adenine, and guanine (CAG) repeats in the HTT gene [79]. Development of CAG repeats within exon 1 of the huntingtin (HTT) gene results in a mutation that causes the polyglutamine tract to elongate, resulting in an HTT protein product that is prone to aggregation [79]. The mutant huntingtin (mHTT) aggregates are accrued throughout the brain of the affected persons, which can disturb transcription process and protein quality control. Those alterations are potentially responsible for the impaired cognitive functions and aberrant motor observed in HD are caused by mutant huntingtin aggregations and concomitant alterations om transcription process and protein quality control [79]. Currently available meditations for HD is palliative as it only inhibits the degree of severeness of symptoms. No meditation/remedy has effectively treated or markedly reversed or arrested the progression of the disease [79]. The mutant huntingtin has been demonstrated to suppress the expression of peroxisome proliferator-activated receptor-coactivator-1 and reduce the concentration of striatal mitochondrial [79, 80]. Similarly, mutant huntingtin has been documented as mutant of HD which has been implicated in the development of neuronal nuclear inclusion in HD as a result of excessive accumulation of cytoplasmic plaque [81]. Notwithstanding the well-proven connection between HD and OS, researches focused at providing treatment for the disease using antioxidant approach have not been successful [82].

#### *Reactive Oxygen Species in Neurodegenerative Diseases: Implications in Pathogenesis… DOI: http://dx.doi.org/10.5772/intechopen.99976*

A number of studies have documented that there exists link between irreversible neuronal damage and elevated oxidative markers [83]. The concentrations of wellestablished indicators of oxidative damage in HD such as neuron-specific enolase (NSE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) have been monitored in one study to determine the benefits of neuro rehabilitation exercise [84]. Furthermore, Cu/Zn-SOD (SOD1) was documented as a possible peripheral indicator of neuronal oxidative damage, with levels considerably higher in HD patients compared to controls, implying a compensatory response to increasing oxidative levels in HD patients [84]. Nevertheless, consideration of SOD1 as an oxidative biomarker in HD remains undecided due to varied results obtained displaying different activity and concentration levels of SOD in HD [85]. After the end of the three weeks regimen neurorehabilitation exercise program, significant reduction in the levels of 8-OHdG and NSE were documented while SOD1 level remained high, indicating the possible neuroprotective role of SOD1 as an antioxidant enzyme mitigating against oxidative stress and scavenging free radicals [84]. Taken together, physical exercise was suggested for HD patients as it may possibly inhibit the disease progression and enhance redox homeostasis [86].

The consequence of HD on brain energy levels has stimulated researchers' interest. In HD patients, reduced glucose consumption and higher lactate levels have been observed, supporting the theory that HD reduces energy levels [81]. According to new researches, oxidative damage is connected to reduced expression of the glucose transporter (GLUT)-3, which consequences lead to lactate build-up and glucose uptake inhibition [87]. Most of ATP synthesis take place via the production of proton motive force through processes of the electron transport chain [88]. mHTT has been demonstrated to perform a crucial function in mitochondrial dysfunction. Panov et al. [89] used electron microscopy to detect that the interaction between mitochondrial membranes and the N-terminal of mHTT leads to mitochondrial calcium abnormalities. Furthermore, mHTT inhibits respiratory complex II in a direct manner [90]. This alteration of the mitochondrial electron transport could lead to over production ROS with concomitant reduction in production of ATP [90].

According to a new mechanism hypothesised in 2015 for mitochondrial damage in HD, oxidative stress could incapacitate glyceraldehyde-3-phosphate dehydrogenase catalytic activities. The incapacitated glyceraldehyde-3-phosphate dehydrogenase is linked with impaired mitochondria which serve as a signalling molecule to initiate the damaged mitochondria towards lysosome engulfment through selective degradation. However, in the existence of mHTT, incapacitate glyceraldehyde-3-phosphate dehydrogenase can react unusually with the long polyglutamine of mHTT at the mitochondrial outer membrane, which result in the inhibition of degradation pathway mediated by incapacitate glyceraldehyde-3-phosphate dehydrogenase. As a result, impaired mitochondria are unable to be engulfed by lysosomes resulting into excessive accumulation of mHTT-expressing cells, thus, facilitating cell death [91]. ROS and mitochondrial alterations can both encourage the positive feedback loops, exacerbating neuronal loss in the cortex and striatum and increases oxidative stress [79]. Excessive generation of ROS and mitochondrial alterations have been implicated in the pathogenesis of HD, however, the event that occurred first remain elusive [92].

3-nitrotyrosine, thiobarbituric acid reactive substances (TBARS), and protein carbonyls are some of the other oxidative biomarkers often used in HD models [93]. Likewise, elevated levels of F2-isoprostane have been reported in the cerebrospinal fluid and brain tissue of Alzheimer's disease and HD patients. As a result, measuring F2-isoprostane could be a useful way to assess the relevance of oxidative stress in HD patients. It's worth noting that F2-isoprostane levels between the HD and control groups may overlap in the early stages of HD development [94]. Thus, interpretation of modifications of oxidative biomarkers in HD should be done with caution due to involvement of oxidative stress in other pathological conditions such as ageing, cancer, and soon. Additionally, oxidative biomarkers alterations levels may not reveal adequate evidence on whether the oxidative alterations perform a significant role on the neuronal cell death or disease pathogenesis [94]. The use of more sensitive and specific indicators or biomarkers would be essential to give detailed information and elucidate the specific functions performed by free radical and oxidative stress in pathogenesis of neurodegenerative diseases, which will provide a mechanistic approach to finding a suitable drug candidate for the effective treatment of HD.

### **6. Role of oxidative stress in pathogenesis of amyotrophic lateral sclerosis**

Amyotrophic lateral sclerosis is a disease in which motor neurons in the anterior horn of the spinal cord gradually diminish [95]. Depending on whether there is a strongly outlined inherited genetic factor, amyotrophic lateral sclerosis is characterised as familial or sporadic. Sporadic amyotrophic lateral sclerosis usually appears between the ages of 50 and 60 [96]. Because the cause of sporadic amyotrophic lateral sclerosis is unknown, finding causal genes and environmental variables has been difficult. About 20% of instances of familial amyotrophic lateral sclerosis were caused by mutations in the SOD1 gene [97]. SOD1 has many activities, including posttranslational modification, energy consumption, controlling cellular respiration, and scavenging superoxide radicals (O2 •–) [98]. Despite the fact that SOD malfunction results in a loss of antioxidant capacity, research suggests that genetic ablation of SOD1 in mice does not result in neurodegenerative diseases [14]. In divergence, the gain-offunction of mutant SOD1 protein has been markedly documented in the motor neuron diseases [14]. For example, a study has exhibited that mutant SOD1 can altered the amino acid biosynthesis of cells in a yeast model and induced cellular destruction, responsible for the neural degeneration in amyotrophic lateral sclerosis [99].

Rac1 is directly regulated by SOD1 via endosome connection, which then activates Nox. Redoxosomes which as Nox-containing endosomes play an essential role in NF-kB-mediated regulation of proinflammatory signals. Nox converts molecular oxygen into O2 •–, which has vital functions in antibacterial activity, enzyme control, and cell signalling (Li et al., 2011). The ratio of reactive oxygen species to antioxidative molecules is balanced under normal physiological conditions. On the other hand, during pathological conditions, there is always rapid fluctuations in ROS levels and disturbances in antioxidant function, which result in elevated level of apoptosis, lipid peroxidation, and DNA damage during disease states [49]. SOD1 is an enzyme which convert O2 •– into hydrogen peroxide (H2O2) and molecular oxygen. SOD1 mutants increase Nox2-dependent ROS generation, which is assumed to be the cause of motor neuron death in amyotrophic lateral sclerosis [100]. SOD1 that has been oxidised or misfolded has been found to cause mitochondrial dysfunction, which has been linked to the aetiology of sporadic amyotrophic lateral sclerosis [101].

Mutant SOD1 may enhance the progression of familial amyotrophic lateral sclerosis via the alterations of signal transduction pathways in motor neurons and in the activity of supportive glial cells [100]. SOD1, for instance, is regarded to be a key cell-signalling molecule with neuromodulatory functions. SOD1 is secreted via the microvesicular secretory pathway, according to studies *in vitro* and in transgenic mice

### *Reactive Oxygen Species in Neurodegenerative Diseases: Implications in Pathogenesis… DOI: http://dx.doi.org/10.5772/intechopen.99976*

models. SOD1 secreted into the environment binds to muscanaric receptors on nearby neurons, increasing intracellular Ca2+ concentration and ERK/AKT signalling [102]. SOD1 preserves motor neuron integrity by activating ERK/AKT signalling, and it has been demonstrated that SOD1 secretion can be enhanced in neurons under oxidative stress conditions [103]. Propofol conditioning treatment was demonstrated to protect the spinal cord against ischemia–reperfusion injury in rats by boosting PI3K/AKT signalling, which could be mediated by enhanced SOD1 activity [104]. Furthermore, oxidative stress can cause neuron cell death by blocking the neuroprotective IGF-I/ AKT pathway, implying that the role of AKT signalling in neurodegeneration should be investigated further [105].

In conclusion, over secretion of ROS in the brain leads to oxidative stress which if not suppressed or inhibited could lead to oxidative damage of essential components of the central nervous system. This can also initiate or enhance some reactions which may have detrimental effects on the physiological functions and health of the brain. These reactions such as neuroinflammation, progressive neuronal cell loss via apoptosis if not abated can exacerbate protein misfolding and formation of protein aggregates resulting into neurodegeneration and associated neurobehavioural incompetence. Considering the pivotal roles of oxidative stress, neuroinflammation, protein misfolding, and apoptosis in neurodegenerative diseases (**Figure 1**), the manipulation of these major players in each of the pathological mechanisms may represent a promising treatment option to slow down neurodegeneration and alleviate associated symptoms.
