A common histopathological hallmark of most neurodegenerative diseases is the presence of aberrant proteinaceous inclusions inside affected neurons. Because these protein aggregates are detected using antibodies against components of the ubiquitin-proteasome system (UPS), impairment of this machinery for regulated proteolysis has been suggested to be at the root of Neurodegeneration. This hypothesis has been difficult to prove in vivo owing to the lack of appropriate tools. The recent report of transgenic mice with ubiquitous expression of UPS-reporter protein should finally make it possible to test in vivo the role of the UPS in neurodegeneration.