Abstract
Therapeutic options remain very limited for the motor neuron disease amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that occurs most often in late middle life. Classic ALS leads to progressive death of motor neurons in the cerebral motor cortex and spinal cord, and the gradual loss of respiratory ability, muscle paralysis and atrophy. Treatment consists of supportive care for respiratory difficulties, symptom relief and nutritional needs. There are currently only two FDA-approved medications for ALS, Riluzole, an anti-glutamatergic compound and Edaravone, an antioxidant, which only provide modest benefit in some patients.  ALS often culminates in death within 2-5 years of clinical presentation, although there exist variants that have a slower progression and better prognosis. ⁠ Approximately 5-10 % of patients with ALS have a familial history (fALS), while the majority of cases, 90-95%, emerge sporadically (sALS), in patients without a family history as a result of indeterminate genetic and environmental etiological causes. Uncovering the genetic variants associated with sALS may be hampered by the methodological approaches employed. For instance, most genetic studies have relied upon short-read and whole exome sequencing platforms, approached more conducive to detecting diseases attributed to one or more single nucleotide polymorphisms. This missing larger structural variants such as deletions, inversions or tandem repeats, which appear likely to play a fundamental role in ALS pathology.  The transactive response DNA binding protein, TDP-43, is an important regulator of RNA processing, including transcription, alternative splicing, microRNA (miRNA) processing, mRNA stability and translation. TDP-43 represents an important target in the etiology of ALS as it forms inclusion bodies or protein aggregates that accumulate in the cytoplasm of motor neurons. This has been defined as a hallmark of both fALS and sALS, even in the absence of a mutation in the TARDBP gene. This chapter will focus on the therapeutic modulation of TDP-43 as a rational approach to treating patients with ALS.
KEYWORDS
amyotrophic lateral sclerosis, ALS,  TDP-43, TARDBP, randomized clinical trial,  cytoplasmic aggregates, mislocalization, N-terminal domain (NTD) and nuclear localization signal (NLS) 
INTRODUCTION
Functions of TDP-43 
The transactive response DNA binding protein, TARDBP gene, encodes the TAR DNA-binding protein of 43 kDa (TDP-43), a ubiquitous nuclear protein that binds to both DNA and RNA, and is important in RNA processing, including transcriptional repression, regulation of non-coding RNA, miRNA biogenesis, alternative splicing, RNA stability, RNA trafficking, and auto-regulation of its own protein production \cite{Mejzini_2019}. The TARDBP protein is expressed early during development, and is involved in a wide range of RNA regulation processes, neurite outgrowth, and is ubiquitously expressed in a diversity of tissues. In addition, TDP-43 is important for genomic integrity maintenance as part of the DNA damage response pathway known as non-homologous end-joining (NHEJ). NHEJ is activated in response to DNA double-stranded breaks (DSB)\cite{Mitra_2019}
Structure of TDP-43