The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis

Abstract

The pathology of the RNA-/DNA-binding protein TDP-43, first implicated a decade ago in the motor neuron disease amyotrophic lateral sclerosis (ALS), has been subsequently linked to a wide spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer's disease (AD), and related demen-tia-associated disorders. ALS, also known as Lou Gehrig's disease, is a progressive, degenerative motor neuron disorder, characterized by a diverse etiopathology. TDP-43 pathology, mediated by a combination of several mutations in the TARDBP gene and stress factors, has been linked to more than 97% of ALS patients. We recently identified, for the first time, the critical involvement of TDP-43 in neuronal genome maintenance and the repair of DNA double-strand breaks (DSBs). Our studies showed that TDP-43 regulates the DNA break-sealing activities of the XRCC4-DNA Ligase 4 (LIG4) complex in DSB repair, suggesting that loss of genomic integrity in TDP-43-associated neurodegeneration may be amenable to a DNA repair-based intervention. In this chapter, we discuss the broader aspects of TDP-43 toxicity-induced pathomechanisms, including the emerging role of TDP-43 in neuronal DSB repair and its synergistic genotoxic effects with other neurodegeneration-associated etiologies that contribute significantly to neuronal dysfunction. We also discuss potential future perspectives and underscore how unraveling the molecular basis and implications of TDP-43-induced genome instability in ALS could guide the development of neuroprotective therapies. 1. TDP-43 pathology: a predominant player in ALS Transactive response DNA-binding protein 43 (TDP-43) is a versatile 43 kDa DNA-/RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. TDP-43's cytosolic aggregation and inclusion body formation are the key pathologic hallmarks of amyotrophic lateral sclerosis (ALS) and fron-totemporal dementia (FTD) [1-3]. In these progressive motor neuron diseases, TDP-43 pathology manifests as the tau-and synuclein-negative and ubiquitin-positive inclusions in the anterior horn, spinal cord, neocortex, and hippocampus regions of the brain. In the last decade, tremendous scientific investigations have been carried out to understand the etiopathologies of TDP-43 toxicity in ALS and FTD. These studies demonstrated that TDP-43 pathology-linked ALS is one of the