Amyotrophic Lateral Sclerosis 4 (ALS4) is a rare, early onset, autosomal dominant form of ALS, a neurodegenerative disorder characterized by the progressive loss of motor neurons in the brain and spinal cord. Dominant, gain-of-function mutations in the RNA-binding protein, senataxin (SETX) cause ALS4, but the mechanistic basis for SETX motor neuron toxicity is unknown. In order to study this phenomenon, an ALS4 mouse model was generated carrying the SETX gene mutation, L389S. These mice exhibit neuromuscular phenotypes and motor neuron degeneration. Primary neurons prepared from these ALS4 mice show signs of neurotoxicity and immunostaining analysis of motor neurons has uncovered nuclear membrane abnormalities. Additionally, a hexanucleotide repeat expansion (HRE) in the gene C9orf72 has been identified as the most common genetic cause of ALS. Separate studies have identified that SETX contributes to C9orf72-ALS disease penetrance and as well acts as a genetic modifier of C9orf72 induced toxicity. Using cells lines and primary neurons we have found that reduced expression of SETX exacerbates C9orf72 HRE dipeptide repeat (DPR) toxicity. Additionally, through density-based fractionation studies we have established the localization of senataxin in the nucleolus and that senataxin forms an interaction with toxic C9orf72 dipeptide repeat proteins.