Major challenges in proving a causal link between neuronal hyperexcitability and cytoplasmic TDP-43 aggregation in the selective vulnerability of human motor neurons in ALS include the elucidation of mechanisms underlying the neural activity-dependent alternative splicing and effects of the sTDP-43 isoforms on TDP-43-containing membraneless organelles. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.