DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

Abstract

Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

“…We do not provide a detailed analysis of the role of DNA damage in neurodegeneration here. For a comprehensive review of this topic, independent of cell death, please see several excellent recent reviews [ 7 , 144 , 148 , 149 ].…”

“…There is extensive evidence for DNA damage in ALS [ 1 , 149 , 286 ]. In addition, DNA damage has been detected at symptom onset in animal models of ALS [ 278 ], implying it may contribute to disease progression.…”

The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

“…There is substantial evidence to indicate the involvement of astrocyte dysfunction in ALS (recently reviewed in [ 296 ]). SOD1 ALS mutations are shown to affect both neuronal and non-neuronal populations, and along with TDP-43 overexpression, SOD1 mutations lead to gliosis and the loss of glial support in the vicinity of motor neurons and interneurons [ 13 , 246 , 297 , 298 , 299 ].…”

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

“…This includes modulation of synaptic transmission, regulation of blood flow to the brain, maintenance of glutamate levels, and delivery of neuroprotective anti-oxidant molecules ( Fernandez-Fernandez et al, 2012 ; Verkhratsky and Nedergaard, 2018 ). Astrocytes appear to play a significant role in toxicity in all ALS types ( Kok et al, 2021 ). Therefore failures in astrocyte energy supply and support functions can undermine neuronal survival and contribute to neuronal injury ( Magistretti and Allaman, 2015 ).…”