A single acetylation-mimic (K145Q) that modulates TDP-43 RNA regulatory functions led to robust aggregation that was sufficient, when targeted to the cytoplasm, to trigger many of the pathological hallmarks associated with TDP-43 proteinopathy including hyper-phosphorylation, recruitment of functionally linked ALS proteins, perturbations of mitochondria, and an associated inflammatory signature. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.