A diverse range of genetic risk factors have been identified for diseases across the frontotemporal dementia (FTD)–amyotrophic lateral sclerosis (ALS) spectrum, but the underlying cellular and molecular processes that culminate in neurodegeneration are still being unravelled. In a new study published in Science, Yong-Jie Zhang, Leonard Petrucelli and colleagues show that variants in two FTD–ALS risk genes — C9orf72 and TBK1, which encodes TANK-binding kinase 1 — impair the functioning of the endolysosomal pathway, leading to pathological intracellular accumulation of TAR DNA-binding protein 43 (TDP43).