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 dementia-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 toxicityinduced 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.

TDP-43 Epigenetic Facets and Their Neurodegenerative Implications

“…TARDBP mutations have been identified mostly in familial ALS patients but also in sporadic FTD, AD, and PD cases, and more than 50 TDP-43 variants have been linked to the incidence of ALS/FTD [ 165 , 166 ]. They are mostly found in the C-term part of the protein, while in the N-term, A90V in the NLS and P112H and D169G have been reported in the RRM1 motif [ 165 ].…”

“…They are mostly found in the C-term part of the protein, while in the N-term, A90V in the NLS and P112H and D169G have been reported in the RRM1 motif [ 165 ]. Functional observations have been made for about twenty of ALS-mutants, as reviewed in [ 165 , 166 ] and for mouse and in vitro models holding TDP-43 mutations, as described in [ 167 , 168 , 169 ], reporting altered normal RNA splicing with or without concomitant cytoplasmic aggregation.…”