A growing body of evidence links vascular dysfunction to neurodegeneration (Zacchigna et al., 2008; Zlokovic, 2008), which prompted us to identify the molecular mechanism leading to the vascular phenotype in loss-of-function mutants of the ALS/FTLD gene tardbp. Given the large overlap in growth and guidance of the vasculature and neurons during development (Carmeliet and Tessier-Lavigne, 2005; Quaegebeur et al., 2011), these changes of pathways in the endothelium of TDP-43 mutants might be also essential in motor neurons and of relevance in ALS. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.