Table 1.

Representative studies that demonstrate the association of specific genetic alterations with oxidative stress in ALS.

Altered gene	Genetic alterations	Experimental model	Observed effects on oxidative stress makers	Reference
SOD1	Mutation: G93A	(i) Transgenic mice	(i) Reduced GSH in the spinal cord and motor neuron cells that correlates with apoptosis-inducing factor translocation, caspase 3 activation, and motor neuron degeneration during ALS-like disease onset and progression	[70]
SOD1	Mutations: A4V, G37R, H48Q, H80R, G85R, D90A, G93A, D124V, D125H, E138Δ, S134N, H46R	(i) NSC-34 motor neuron-like cell line	(i) MutSOD1s lowered the GSH/GSSG ratio in mitochondria of cells	[69]
SOD1	Mutations: G1H, G1L, A4V, H46R, G93A, frame-shift 126 mutation	(i) Motor neurons from 40 sALS and 5 mutated SOD1 sALS patients (frame-shift 126 mutation and A4V) (ii) Transgenic rats (H46R/G93A) (iii) Transgenic mice (G1H/G1L-G93A)	(i) The number of motor neurons with negative expression of antioxidant enzymes (Prxll and GPxl) increased with ALS disease (ii) Neurons with higher expression of Prxll and GPxl were less susceptible to oxidative stress	[98]
TDP-43	Mutations: M33V, Q331K	(i) TDP-43Q331K mice (ii) Primary astrocyte cultures from TDP-43Q331K mice (iii) Fibroblasts from pre- and postsymptomatic ALS patient fibroblasts harboring a TDP-43M337V mutation	(i) Increased transcript expression of Nrf2 signaling-related genes (NFE2L2, HMOX1, GCLM, and NQO1) in the spinal cord of transgenic mice (ii) No change in protein expression levels of HO-1, GCLM, GPx1, and NQO1 antioxidant proteins in transgenic mice (impaired protein translation of antioxidants) (iii) Decreased total GSH levels in fibroblasts from pre- and postsymptomatic patients (iv) Decreased total GSH levels in primary astrocytes from transgenic mice	[116]
TDP-43	Mutation: M337V	(i) NSC-34 motor neuron-like cell line	(i) Decreased nuclear translocation of Nrf2, total Nrf2, cytoplasmic Nrf2, and downstream phase II detoxifying enzyme (NQO1) (ii) Increased lipid peroxidation products	[115]
TDP-43	Mutations: Q331K, M337V	(i) NSC-34 motor neuron-like cell line	(i) Mitochondrial dysfunction, oxidative damage, and nuclear accumulation of Nrf2 in cells (ii) Downregulation of HO-1, that could not be restored by sulforaphane (iii) Reduction of LDH and lipid peroxidation products by sulforaphane	[117]
C9orf72	GGGGCC hexanucleotide repeat expansion in noncoding region	(i) iPSC-derived astrocytes from C9orf72-mutated fALS patients and nonaffected donors	(i) Decreased secretion of antioxidant proteins (SOD1, SOD2, and GSH) in mutant C9orf72 astrocytes (ii) Increased ROS levels in mutant C9orf72 astrocytes (iii) Conditioned media of mutant C9orf72 astrocytes increased ROS levels in wild type motor neurons (iv) Oxidative stress was increased in an age-dependent manner (v) poly(GR) in C9orf72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress	[129]
C9orf72	GGGGCC hexanucleotide repeat expansion in noncoding region	(i) iPSCs-derived motor neurons isolated from C9orf72-mutated fALS patients (ii) iPSC-derived control neurons expressing (GR)80 and dipeptide repeat (DPR) protein	(i) Increased mitochondrial ROS levels cause DNA damage in both models (ii) Prevention of DNA damage by an antioxidant (Trolox)	[128]
ANG	Human wild type ANG (wANG) and its variant K40I (mANG)	(i) SH-SY5Y neuroblastoma cells and NSC-34 motor neuron-like cell line	(i) wANG prevented cell death under H2O2-induced oxidative stress (ii) Increased hydrogen peroxide-induced cell damage in mutant ANG motor NSC-34 neuron-like cell line	[131]

fALS: familial ALS; GCLM: glutamate-cysteine ligase modifier subunit; GPX1: glutathione peroxidase-l: HMOX1: heme oxygenase-1; iPS: induced pluripotent stem cell; LDH: lactate dehydrogenase; NQO1: NAD(P)H quinone dehydrogenase 1; PrxII: peroxiredoxin-ll; sALS: sporadic ALS.