Drug Target and Biomarker: SOD1 (G6647)

Target Name: SOD1

NCBI ID: G6647

Drug Target and Biomarker: SOD1

SOD1 mutations, such as mSOD1, can trigger endoplasmic reticulum stress and unfolded protein response (UPR), leading to the accumulation of misfolded mutant proteins and activation of autophagy pathways [1A].

Oxidative stress and mitochondrial dysfunction, caused by mutations in SOD1, can activate autophagy and trigger mitophagy, which helps in clearing damaged mitochondria [1B].

Mutations in RNA-binding proteins, including SOD1, can lead to defects in RNA metabolism and alter the dynamics of stress granules, potentially affecting autophagy [1C].

DNA damage, either as a result of pathogenic mutations or oxidative stress, is a common feature in SOD1 mutations and can activate autophagy through the AMPK pathway [1D].

The metalation and activation of SOD1 is facilitated by the interaction with copper chaperone for SOD1 (CCS) protein, leading to the formation of fully metalated holo-SOD1 monomers that can homodimerize.

SOD1 regulation can be influenced by post-translational modifications (PTMs), including those driven by factors such as DNA damage, amino acid starvation, and metabolic fitness.

Extracellular vesicles (EVs) play a role in ALS pathology by spreading mutant proteins implicated in ALS, including mutant SOD1, TDP-43, FUS, and DPRs from expanded C9orf72.

SOD1 oxidation is modulated by the levels of Cd2+, Zn2+, and metallothioneins (MTs), with excess Cd2+ causing redox imbalance and oxidation of SOD1, while supplementation of excess Zn2+ and induction of MTs can prevent SOD1 oxidation.

In prion-like diseases, like ALS, the misfolding of SOD1 leads to a reduction in protein function, which may contribute to the pathology.

Normally folded prion protein (PrPC) is reduced in abundance in prion disease paradigms, and this reduction may be linked to the neuroprotection functions associated with PrPC.

Misfolding of proteins like PrPC and SOD1 can also impact the functions of the proteins they interact with, which may be neuroprotective or essential for neuron survival.

It is unclear if the abundance of normally folded SOD1 decreases with disease progression, but misfolded SOD1 conformers with reduced function could explain the loss-of-function component in ALS pathology.

SOD1 plays a role in the detoxification of reactive oxygen species (ROS), and its upregulation, along with other proteins like Prdx1, contributes to the lifespan of red blood cells.

In glioblastoma-derived cells, the interaction between neurotransmitter substance P (SP) and its receptor NK1R can lead to an increase in intracellular ROS levels by suppressing the enzymatic activities of catalase and SOD. However, blocking NK1R using a drug called aprepitant can restore the oxidative balance and reduce the survival and proliferative capacity of these cells.

ALS-related SOD1 G93A mutation impairs the binding of VDAC1 and HK1, leading to mitochondrial dysfunction. However, a peptide called NHK1 can inhibit the binding of SOD1 G93A to VDAC1 and improve mitochondrial function and cell viability.

In patients with oral cancer, lower SOD enzyme activity has been reported, suggesting a potential role of SOD in the progression of oral cancer.

Protein Name: Superoxide Dismutase 1

Functions: Destroys radicals which are normally produced within the cells and which are toxic to biological systems

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