The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis - Recent Advances and Therapeutic Challenges [Working Title]
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,
... 3 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. 2 most complex neurological diseases due to TDP-43 pathomechanisms overlapping with other ALS-causing genes, such as C9orf72 [4-6], valosin-containing protein (VCP) [7-9], fused in sarcoma (FUS) , optineurin (OPTN) , ubiquilin 2 (UBQLN2) [12, 13], and ataxin 2 (ATXN2) [14, 15]. Strikingly, TDP-43 pathology has been detected in more than 97% of sporadic ALS cases (>90%), making it a predominant player in most ALS patients. Familial and sporadic ALS Due to highly overlapping symptoms, determining the sporadic or familial nature of the ALS disease at its time of onset is difficult based on clinical features alone. Familial ALS (FALS) is predicted based on genetic screening for TARDBP mutation(s) in the patient and matching the same mutation in the family member(s) with a positive clinical/medical history of neurodegeneration and dementia in the juvenile or early stage of life. Race, age, and gender are risk factors for progression of FALS. FALS incidences vary significantly from 5 to 10% among all ALS cases. The disease is more common in Caucasian men and women than African, Asian, and Hispanic populations . Notably, clusters of ALS incidences have been associated with socio-economic conditions along with race. According to Centers for Disease Control and Prevention, ALS prevalence is highest in the Midwest and Northeast of US main land (5.7 and 5.5 per 100,000 population, respectively)  . In Europe, the prevalence of FALS was lower in the southern part  . Studies show that men are at slightly higher risk than women, with an average age of onset ~60 years. Patients usually survive for 1.5-4 years after diagnosis, depending on the disease aggressiveness  . FALS associated pathology affects anterior horn motor neurons in the cervical and lumbosacral regions in the spinal cord, frontal cortex, and cranial nerve motor neurons in the pons and medulla segments of brainstem. Both sporadic ALS (SALS) and FALS pathologies are associated with upper and/or lower motor neurons of the spinal cord. Upper motor neuron diseases accompany degeneration of lateral corticospinal tracts leading to hyperreflexia/spasticity and cardiac arrest. Conversely, lower motor neuron death leads to muscle atrophy and denervation. FALS cases fall into to three categories, namely, autosomal dominant, autosomal recessive, and X-linked dominant. Autosomal dominance is the most common inherited pattern among the FALS cases, where a mutation in one copy of the ALS-linked gene is sufficient to develop ALS conditions. These patients usually have a strong positive family history and their children bear 50% risk of developing ALS. However, autosomal dominance can also happen in apparently sporadic ALS (because the genetic inheritance is unknown or poor medical history) with de novo dominant mutation(s). In such cases, patients' siblings may have very low risk but children may have up to 50% risk of developing ALS. To date, more than 50 mutations in TARDBP gene have been identified in ALS etiopathologies  . In addition, a study on a German cohort of non-SOD1 FALS patients revealed mutations in TARDBP, suggesting TARDBP gene mutation screening should be crucial among non-SOD1 FALS patients  . The known TARDBP mutations in FALS are G290A, G298S, A315T, M337V, N345K, A382T, and I383V; some of the common mutations identified in SALS are D169G, G287S, G294A, Q331K, G348C, R361S, and N390S/D (Figure 1 )        . Most of these TARDBP mutations are located within exon 6, as commonly found in Caucasian and European ALS patients; however, a large cohort of Han Chinese population with non-SOD1 SALS did not show any such mutations in exon 6  . SALS has been reported in an increasing number among people exposed to lead or other heavy metals    , smoking [32, 33] , and pesticides  . Increased exposure to organochlorine pesticides, biphenyls, and brominated flame retardants DOI: http://dx.