Discovery of Therapeutics Targeting Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic Review

Abstract

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.

Keywords: antioxidant pathway and therapy; autosomal recessive cerebellar ataxia; genetic mutation; oxidative stress; preclinical model; rare neurodegenerative disease.

Figure 1

Mutation in the ATM gene in the pathogenesis of A-T. The defective ATM gene results in the disruption of DNA repair mechanisms that are critical for maintaining the integrity of genomic DNA and subsequent accumulation of unregulated DNA damage. An absence or deficiency of ATM protein contributes to the impairment of mitochondria, leading to excessive production of ROS. Dysregulated ROS signaling further accelerates DNA damage. ATM, ataxia-telangiectasia mutated; ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; MMP, mitochondrial membrane potential; ROS, reactive oxygen species.

Figure 2

Mutations in the APTX and SETX genes in pathogenesis of AOA1 and AOA2, respectively. The defective genes result in the disruption of DNA repair mechanisms that are critical for maintaining the integrity of genomic DNA and subsequent accumulation of unregulated DNA damage. An absence or deficiency of APTX or SETX protein contributes to the impairment of mitochondria leading to excessive production of ROS. AOA, ataxia with oculomotor apraxia, APTX, aprataxin, ATP, adenosine triphosphate; SETX, senataxin, DNA, deoxyribonucleic acid, MMP, mitochondrial membrane potential; ROS, reactive oxygen species.

Figure 3

Mutation in the TTPA gene in the pathogenesis of AVED. An absence or deficiency of TTPA protein prevents the transfer of α-tocopherol from chylomicrons to very-low-density lipoproteins (VLDLs). Insufficient circulation of α-tocopherol contributes to vitamin E deficiency, which can increase the susceptibility to oxidative stress. TTPA, α-tocopherol transfer protein, VLDLs, very-low-density lipoproteins, ROS, reactive oxygen species.

Figure 4

Mutation in the SACS gene in the pathogenesis of ARSACS. An absence or deficiency of SACS protein contributes to the excessive production of ROS, modification of neurofilaments and mitochondrial impairment. These events lead to further generation of ROS and disruption of OXPHOS. ATP, adenosine triphosphate; MMP, mitochondrial membrane potential; SACS, sacsin; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

Figure 5

Mutation in the FXN gene in the pathogenesis of FRDA. An absence or deficiency of frataxin protein contributes to the disruption of FeS clusters biogenesis, disrupting oxidative OXPHOS. In addition, the protein deficiency also contributes to abnormal accumulation of iron and mitochondrial impairment, leading to excessive production of ROS. ATP, adenosine triphosphate; FXN, frataxin; FeS, iron-sulfur; MMP, mitochondrial membrane potential; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

Figure 6

PRISMA flow chart for the identification of relevant studies.

Figure 7

Antioxidant therapies against A-T. The defective ATM gene leads to the disruption of DNA damage response and repair, excessive production of ROS, and impairment of mitochondria. Antioxidant therapies can modulate ATM, NRF2, TERT, serine-1981, serine-824, KAP1 and γ-H2A.X expressions, and mitochondrial impairment, resulting in the restoration of DNA damage response and repair, antioxidant enzyme and gene levels, mitochondrial function, and telomere activity and elongation. This also leads to the attenuation of ROS production and pro-apoptotic activities. ATM, Ataxia-telangiectasia mutated; ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; GCLC, glutamyl-cysteine ligase catalytic subunit; GCLM, glutamyl-cysteine ligase modifier subunit; GSEs, genetic suppressor elements; GSH, glutathione; GSR, glutathione reductase; GSS, glutathione synthetase; IL, interleukin; KAP1, KRAB-associated protein 1; KEAP1, Kelch-like ECH-associated protein 1; MMP, mitochondrial membrane potential; NQO1, NAD(P)H quinone oxidoreductase 1; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor erythroid 2–related factor 2; OGG1, 8-oxoguanine DNA glycosylase-1; ROS, reactive oxygen species; SOD1, superoxide dismutase 1; TERT, telomerase reverse transcriptase; γ-H2A.X, gamma-H2A histone family member X; 8-oxoG, 8-oxoguanine.

Figure 8

Antioxidant therapies against FRDA. (a) Regulation of KEAP1–NRF2 complex, mTOR expression, lipid peroxidation, mitochondrial impairment and autophagy by antioxidant therapies results in the dissociation of KEAP1–NRF2 complex, restoration of mitochondrial respiration and biogenesis, and attenuation of lipid peroxidation. The dissociation of the KEAP1–NRF2 complex leads to the upregulation of downstream targets responsible for increased levels of antioxidant enzyme and gene, and attenuation of ROS production and pro-apoptotic activities. (b) Regulation of FXN expression and antioxidant enzymes by antioxidant therapies results in the promotion of FeS clusters biogenesis and restoration of mitochondrial function. Increased protein level of frataxin restores calcium regulation and attenuates neurofilament aggregate formation. The events ultimately lead to the attenuation of ROS production and pro-apoptotic activities. AMPK, AMP-activated protein kinase; ATG7, autophagy related 7; ATP, adenosine triphosphate; CAT, catalase; Cyt c, cytochrome c; DJ-1, protein deglycase; DRP1, dynamin-related protein 1; FXN, frataxin; GCL, γ-glutamyl cysteine ligase; GPX4, glutathione peroxidase 4; GRP75, glucose-regulated protein 75; GSH, glutathione; GSSG, oxidized glutathione; GSTM1, glutathione S-transferase mu 1; HO-1, heme oxygenase-1; KEAP1, Kelch-like ECH-associated protein 1; LC3, microtubule-associated protein 1A/1B-light chain 3; MFN1, mitofusin 1; MMP mitochondrial membrane potential; mTOR, mammalian target of rapamycin; NDUFS3, NADH: ubiquinone oxidoreductase core subunit s3; NFS1, cysteine desulfurase; NOQ1, NAD(P)H quinone oxidoreductase 1; NRF2, nuclear factor erythroid 2–related factor 2; NSF, N-ethylmaleimide-sensitive fusion protein; OGDH, 8-oxoglutarate dehydrogenase E1 component; PDH, pyruvate dehydrogenase; PGC-1α, peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1 alpha; PRDX2, peroxiredoxin 2; ROS, reactive oxygen species; SOD, superoxide dismutase; SRXN1, sulfiredoxin; TXNRD1, thioredoxin reductase 1.