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Abstract
As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. Cells have different mechanisms to deal with this protein aggregation, where the molecular chaperone machinery constitutes the first line of defense against misfolded proteins. Proteins that cannot be refolded are subjected to degradation and compartmentalization processes. Amyloid formation has traditionally been described as responsible for the proteotoxicity associated with different neurodegenerative disorders. Several mechanisms have been suggested to explain such toxicity, including the sequestration of key proteins and the overload of the protein quality control system. Here, we review different aspects of the involvement of amyloid-forming proteins in disease, mechanisms of toxicity, structural features, and biological functions of amyloids, as well as the cellular mechanisms that modulate and regulate protein aggregation, including the presence of enhancers and suppressors of aggregation, and how aging impacts the functioning of these mechanisms, with special attention to the molecular chaperones.
Highlights
The process of aging is defined as a time-dependent functional decline eventually resulting in an increased vulnerability to death
Some neurodegenerative diseases, including Alzheimer (AD), Parkinson (PD), and Huntingtin disease (HD), share as hallmark the appearance of protein aggregates with fibrillary amyloid-like structures in the brain. These amyloid fibrils are composed of aggregation-prone proteins, such as mutant huntingtin (HTT) in Huntington disease, α-synuclein in Parkinson disease, and amyloid-beta (Aβ) in Alzheimer disease (Scherzinger et al, 1999; Chiti and Dobson, 2006; Goedert and Spillantini, 2006; See Table 1 for a list of aggregation-prone proteins involved in neurodegenerative diseases)
Two other common nonneuropathic systemic amyloidosis are caused by transthyretin amyloidosis (ATTR) and serum amyloid A protein (SAA), both proteins are produced in the liver and affect various organs, in ATTR heart failure is most common whereas SAA often results in renal failure
Summary
The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. We review different aspects of the involvement of amyloid-forming proteins in disease, mechanisms of toxicity, structural features, and biological functions of amyloids, as well as the cellular mechanisms that modulate and regulate protein aggregation, including the presence of enhancers and suppressors of aggregation, and how aging impacts the functioning of these mechanisms, with special attention to the molecular chaperones
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