Researchers at CIC bioGUNE and ATLAS Molecular Pharma, in collaboration with European centres, have described two new cases of Variably Protease-Sensitive Prionopathy (VPSPr), an exceptional form of prion disease that manifested as upper motor neuron syndrome and frontotemporal dementia. The patients developed progressive motor disturbances, insomnia and cognitive impairment, without any suspicion of a prion origin during their lifetime. The diagnosis was confirmed after death by neuropathological and biochemical studies, highlighting the need to consider this pathology in cases that mimic ALS or frontotemporal dementias.