Protein aggregation disorders

Protein aggregation disorders are a group of diseases that arise because of or are associated with the misfolding and aggregation of one or more proteins. They are believed to result from the failure of proteins to reach their active state or from the accumulation of abnormally folded proteins. Despite the strong connection between protein misfolding and aggregation and disease, the manner by which it results in disease is still unknown. The “amyloid hypothesis” states that the aggregation of proteins into an ordered fibrillar structure is causally related to aberrant protein interactions that culminate in neuronal dysfunction and ultimately neurodegeneration. Evidence from a variety of diseases suggests that specific alterations in the primary sequence of cellular proteins, posttranslational modifications, or defective interactions with other proteins can impose conformational constraints that alter the normal function/biology of these proteins and facilitate aggregation. Protein aggregation disorders include Alzheimer's disease (AD), synucleinopathies [Parkinson's disease (PD)], and prion diseases. Accumulation of Aβ in the brain is the primary culprit of AD-related pathogenesis, including neurofibrillary tangles (NFT) formation, synapse loss, and neuronal cell death. In PD, the disconnection between pathogenesis and α-synuclein inclusion formation adds support for roles of α-synuclein oligomers in toxicity and pathogenesis. The accumulation of PrPSc (prion protein) in the brain is the hallmark of prion diseases, but, as in other neurodegenerative diseases, whether it is directly responsible for the devastating pathology is still unclear.