Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

Abstract

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target.

Diallyl Trisulfide Protects Rat Brain Tissue against the Damage Induced by Ischemia-Reperfusion through the Nrf2 Pathway

“…According with our results, there is evidence indicating that SOD1 is translocated to the nucleus in primary cultured human lens epithelial cells (HLEC) after treatment with 17β-estradiol [47]. The nuclear translocation of SOD1 requires its phosphorylation by the ataxia-telangiectasia-mutated/checkpoint kinase 2 (ATM/Chk2) [48], two kinases activated by oxidative stress [49] and DATS [50]. There are reports indicating that the physiological role of nuclear SOD1 is associated with the decrease in the DNA damage induced by ROS in yeast [51] and in neuroblastoma SH-SY5Y cells [48].…”

“…The nuclear translocation of SOD1 requires its phosphorylation by the ataxia-telangiectasia-mutated/checkpoint kinase 2 (ATM/Chk2) [48], two kinases activated by oxidative stress [49] and DATS [50]. There are reports indicating that the physiological role of nuclear SOD1 is associated with the decrease in the DNA damage induced by ROS in yeast [51] and in neuroblastoma SH-SY5Y cells [48]. Another possibility of the role of SOD1 in the nucleus is its ability to function as a transcription factor.…”

Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach

“…A promising strategy to improve intracerebral drug delivery is represented by gene therapy, which, by altering or inducing the expression of specific genes using modified viral vectors derived especially from adeno-associated viruses (AAV), can have a great role in neuroprotection, restoration, and correction of the underlying pathogenic mechanisms. For example, SOD1 is known to play an important role in the progression of ALS [37] and an injection of AAV carrying a SOD1 silencing RNA in mice expressing a mutant SOD1 produces long-term suppression of MNs disease [38]. Moreover, the development of a convection-enhanced delivery (CED) in the 1990s and of a real-time magnetic resonance imaging (MRI)-guided CED in recent years, has allowed for monitoring of the infusion of the drug via co-administration of an MRI-contrast agent to have a specified therapy in the anatomical regions of interest [34].…”

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

“…Related to this, the native, soluble isoforms of certain disease-associated proteins, including Tau, FUS, SOD1 and α-synuclein, have been directly linked to genome maintenance in vivo, and genomic instability caused by their mutant species has been attributed to their effective loss from the nucleus (Bordoni et al 2019;Maina et al 2016;Schaser et al 2019;Wang et al 2018). Importantly, it is not always understood if this is a direct consequence of their misfolding, or a result of their accelerated aggregation in the cytoplasm.…”