**4. Role of oxidative stress in pathogenesis of spinocerebellar ataxia disease**

Spinocerebellar ataxia is a progressive neurodegenerative illness caused by an autosomal dominant gene. Cognitive impairments, dysarthria, osculomotor abnormalities, and ataxic gait are all well-known signs of spinocerebellar ataxia, which can lead to mortality. Based on genetic descriptions, about 20 forms of spinocerebellar ataxia have been identified [72, 73]. The main pathogenic mutation in spinocerebellar ataxia has been linked to the expansion of repeated CAG trinucleotides [74]. The mutant ataxin 1 (ATXN1) protein, which has an enlarged polyglutamine, is overexpressed as a result of the mutation from expansion of repeated CAG trinucleotides. RAR-related orphan receptor alpha, which plays a key role in Purkinje cell activities, can be affected by mutant ataxin 1. Reduced RAR-related orphan receptor alpha gene expression has been linked to cerebellar hypoplasia and ataxia [75].

Majority of spinocerebellar ataxia are thought to be genetic disorders linked to ATXN mutations, however, different pathogenic pathways involving mitochondrial malfunction have been hypothesised [75]. Hakonen et al. [76] reported mitochondrial DNA depletion and respiratory complex I deficiency in the brain of infantile-onset spinocerebellar ataxia patients. Small concentration of ROS has been documented to be beneficial for cellular activities including cell signalling, nonetheless, higher concentration is dangerous to the brain being neurotoxic and have been established to cause neurodegeneration [49]. A study conducted by Stucki et al. have reported marked mitochondrial alterations and excessive accumulation of oxidative stress in the Purkinje cells of Spinocerebellar ataxia 1. It was suggested that there exists a connection between oxidative stress mediated mitochondrial impairments and the progression of spinocerebellar ataxia [75]. Similarly, the study evaluated the possible

neuroprotective roles of MitoQ (a mitochondrial antioxidant) in a spinocerebellar ataxia mouse model. The result revealed long-term treatment of MitoQ markedly improved mitochondrial morphology and enhanced its functions in Purkinje cells resulting in amelioration of spinocerebellar ataxia 1-related symptoms including motor incoordination [75]. This report demonstrated the neuroprotective potential of mitochondria-targeted antioxidants as a potential treatment for spinocerebellar ataxia 1.

Similar to previous neurodegenerative diseases discussed, pathogenesis of spinocerebellar ataxia is associated with mitochondrial dysfunction [77]. For instance, Friedreich ataxia, is characterised by the absence of frataxin, an iron transporter protein located on the mitochondrial inner membrane. Decrease in the level of frataxin, leads to increase in concentration of iron in the mitochondrial matrix, thus stimulating the Fenton reaction which convert of H2O2 to ˙ OH. The highly reactive ˙ OH molecules can compromise the efficiency of energy production in neuron cells by causing oxidative damage to mitochondria [77]. Therefore, antioxidant supplementation, such as coenzyme Q10 and tocopherol, has been proven to increase energy production in many Friedreich ataxia patients by decreasing oxidative stress and restoring mitochondrial activity [78].

Because the brain contains so many mitochondria, mitochondrial malfunction can have a considerable deleterious impact on the nervous system. ROS are created spontaneously by the mitochondrial respiratory chain and are vital for sustaining mitochondrial function as well as brain cell resilience. However, there has been little study done to determine the potential involvement of ROS in spinocerebellar ataxia illnesses and establish optimum therapy options. More research is required to better understand the redox mechanisms driving various forms of spinocerebellar ataxias, with an emphasis on ROS-targeted therapy.
