Abstract
Accumulation of specific proteins has replaced loss of specific populations of neurons in the definition of most neurodegenerative diseases. In some cases, the amino-acid sequence of the protein that accumulates is altered by a mutation in the gene that codes for it but most generally, the primary structure is normal. Much evidence from human neuropathology has been collected over the years indicating that the progression of the lesions in such neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy follow the neuroanatomical connections. More recently, injection of aggregates of the specific proteins in the brain of experimental animals has been attempted in various experimental settings. Brain homogenates containing Aβ aggregates induce the early development of Aβ deposits in APP transgenic mice. Brain homogenates from various human tauopathies induce tau aggregates in transgenic mice expressing normal human tau. Finally, synthetic preformed fibrils of alpha-synuclein initiate the development of alpha-synuclein accumulation resembling Parkinson's disease in wild-type mice. Experiments in cell cultures suggest that the protein has to be in some specific state of oligomerization or fibrillation to be endocytosed and transported by the neuron. These data suggest that the protein that accumulates in a specific disease is initially misfolded and that this misfolding contaminates normal protein in a prion-like manner – in some cases through the neuronal connections.
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