A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS

Abstract

Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.

Keywords: ALS; DNA damage; DNA ligase; mitochondria; neurodegeneration.

Figure 1.

Schematic representation of our recent study, which provide new molecular insights into the role of FUS in mitochondrial genome maintenance and the implications of FUS mutations in ALS. FUS is required for optimal mtDNA ligation in healthy neurons, facilitating efficient DNA repair. However, familial mutations in ALS causes mtDNA ligation defects, leading to overall mitochondrial dysfunction. Expression of mitochondria-targeted Lig1 (MTS Lig1) rescues mtDNA repair and restores function. Abbreviations: ALS, amyotrophic lateral sclerosis; FUS, fused in sarcoma.