Protein misfolding in neurodegenerative diseases

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Abstract
A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone‐specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.

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