We are studying neurodegeneration from the standpoint of proteins that adopt a self-replicating pathological conformation. All major neurodegenerative diseases are relentlessly progressive, and virtually all are linked to the accumulation of protein amyloids, which are ordered, paracrystalline assemblies that typically are rich in beta sheet structure. Over 10 years ago we wondered why neurodegenerative diseases feature pathology that spreads through the brain. We hypothesized that prion mechanisms could explain myriad features of common diseases such as the tauopathies and synucleinopathies: the accumulation of intracellular amyloids; progression through neural networks and connected cells; and phenotypic diversity. The basic biology of prions, infectious proteins that replicate distinct pathological structures and cause distinct patterns of neuropathology, serves as a model that provides new ideas about the basis of neurodegeneration in common disorders.
The human prion protein (PrP) causes neurodegeneration based on trans-cellular propagation of pathology. Pathology begins with a “seed” that can arise spontaneously within the brain, or, much more rarely, can be introduced by environmental exposure, i.e. infection. The seed acts as a template to convert normal PrP to a new structure that causes disease, and can spread pathology throughout the brain. We have discovered that the tau protein, which accumulates in intracellular and extracellular amyloids in a variety of neurodegenerative diseases, has essential characteristics of PrP. This can explain the relentless progression and phenotypic diversity of the myriad disorders termed “tauopathies,” which include Alzheimer's disease, the frontotemporal dementias, and chronic traumatic encephalopathy. The same principles apply to other disease-causing proteins that form amyloid structures, such as α-synuclein.