Prion diseases are characterized by the spreading and the accumulation of the pathological isoform (PrPSc) of the cellular prion protein (PrPC). Accumulation of PrPSc in the brain results in loss of neurons, astrogliosis, PrP amyloid plaques and spongiform degeneration of the tissue. Despite many advances in the study of neurodegeneration caused by prions, knowledge about the physiological function of the PrPC is still lacking. It is well established that the absence of PrPC rescues the toxic effect of prions. A neuroprotective function of PrPC as well as a role in cell signalling has been suggested. Ubiquitylation is a cellular process to address proteins to different fates, e.g. degradation, aggregation, localization, DNA damage repair. It is known that PrPC is ubiquitylated via the canonical ubiquitin code and addressed to proteasomal degradation. In this work we investigated the relationship between PrPC and the Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), a player of the atypical ubiquitylation that drives ubiquitylated substrates to a different cellular fate. TRAF6 ubiquitylates α-synuclein and huntingtin as well as their pathological isoforms. TRAF6 is found in cellular aggregates of these proteins. Through in vitro and in vivo experiments we found that full-length and cytosolic form of PrPC are able to interact with TRAF6 and are present in cellular aggregates. Moreover, full-length PrPC is a substrate of TRAF6 ubiquitylation. These findings open the door to the identification of a putative common mechanism for neurodegenerative diseases, suggesting a role for TRAF6 in regulating the fate of PrPC and of other neurodegenerative-associated proteins.
