Target Name: SOD1
NCBI ID: G6647
Other Name(s): ALS, Sod1, SOD
Drug Target Analysis Report Drug Target Analysis Report Content

About the Target

Based on the provided context information, the key viewpoints regarding SOD1 are as follows:

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 [2].

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 [3].

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 [4].

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 [5].

[1] Cross-talk between autophagy and other pathogenic mechanisms in amyotrophic lateral sclerosis (ALS)
[2] Transitional free-energy landscapes of SOD1 metalloforms and CCS-dependent SOD1 maturation
[3] PTM-driven mechanisms of SOD1 regulation
[4] EVs in ALS pathology
[5] Cd2+-induced SOD1 oxidation is modulated by Zn2+ and MT levels
Based on the provided context information, the following key viewpoints can be extracted regarding SOD1:

In prion-like diseases, like ALS, the misfolding of SOD1 leads to a reduction in protein function, which may contribute to the pathology [6].
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 [6].
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 [6].
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 [6].
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 [7].
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 [8].
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 [9].
In patients with oral cancer, lower SOD enzyme activity has been reported, suggesting a potential role of SOD in the progression of oral cancer [8].

[6] Context Information, [7] Context Information, [8] Context Information, [9] Context Information.

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