Seeding and propagation of lesions in neurodegenerative diseases: a new paradigm

International audienceSpecific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aβ peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aβ peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aβ, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought