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Unfolding the role of protein misfolding in neurodegenerative diseases

Unfolding the role of protein misfolding in neurodegenerative diseases Recent studies of the molecular mechanism of brain degeneration in neurodegenerative diseases have found several common features in this group of clinicopathologically different illnesses, which includes Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopathies. Evidence from neuropathological and genetic studies, as well as from the generation of transgenic animal models, strongly supports the hypothesis that diverse neurodegenerative diseases are caused by the misfolding, aggregation and accumulation in the brain of an underlying protein. In vitro structural studies have shown that misfolding and aggregation involve a large structural rearrangement of the protein, forming cross-β amyloid-like fibrils, which seems to be the common end point of protein aggregation in these diseases and can result in the accumulation of aggregates intra- or extracellularly. The misfolding and aggregation process depends on either hydrophobic interactions or hydrogen bonding between the protein molecules. Protein misfolding and aggregation follows a seeding–nucleation mechanism modulated by several environmental factors and involving the formation of at least two intermediates: soluble oligomers and protofibrils. The mechanism by which protein misfolding and aggregation is involved in neurodegeneration is unknown, but at least three general models can be proposed: loss of the physiological activity of the misfolded protein, acquisition of neurotoxicity upon protein misfolding and chronic brain inflammation triggered by the accumulation of protein deposits. Although most of the data support the gain of a neurotoxic activity as the most likely mechanism of neurodegeneration, the nature of the toxic species is unknown. Recent findings indicate that soluble microaggregates, rather than large protein deposits, might be mostly implicated in neuronal damage. Several strategies are being pursued to inhibit and/or reverse protein misfolding and aggregation, with the hope that some of them will result in the generation of drugs that will be useful for the treatment of neurodegenerative diseases. Additional research is necessary to demonstrate definitively the involvement of protein misfolding and aggregation as a common cause of neurodegenerative diseases. Future work should also focus on understanding the contribution of alternative protein folding in other diseases and in normal cellular functioning. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Neuroscience Springer Journals

Unfolding the role of protein misfolding in neurodegenerative diseases

Soto, Claudio
Nature Reviews Neuroscience , Volume 4 (1) – Jan 1, 2003
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References (165)

Publisher
Springer Journals
Copyright
Copyright © 2003 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Neurosciences; Behavioral Sciences; Biological Techniques; Neurobiology; Animal Genetics and Genomics
ISSN
1471-003X
eISSN
1471-0048
DOI
10.1038/nrn1007
Publisher site
See Article on Publisher Site

Abstract

Recent studies of the molecular mechanism of brain degeneration in neurodegenerative diseases have found several common features in this group of clinicopathologically different illnesses, which includes Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopathies. Evidence from neuropathological and genetic studies, as well as from the generation of transgenic animal models, strongly supports the hypothesis that diverse neurodegenerative diseases are caused by the misfolding, aggregation and accumulation in the brain of an underlying protein. In vitro structural studies have shown that misfolding and aggregation involve a large structural rearrangement of the protein, forming cross-β amyloid-like fibrils, which seems to be the common end point of protein aggregation in these diseases and can result in the accumulation of aggregates intra- or extracellularly. The misfolding and aggregation process depends on either hydrophobic interactions or hydrogen bonding between the protein molecules. Protein misfolding and aggregation follows a seeding–nucleation mechanism modulated by several environmental factors and involving the formation of at least two intermediates: soluble oligomers and protofibrils. The mechanism by which protein misfolding and aggregation is involved in neurodegeneration is unknown, but at least three general models can be proposed: loss of the physiological activity of the misfolded protein, acquisition of neurotoxicity upon protein misfolding and chronic brain inflammation triggered by the accumulation of protein deposits. Although most of the data support the gain of a neurotoxic activity as the most likely mechanism of neurodegeneration, the nature of the toxic species is unknown. Recent findings indicate that soluble microaggregates, rather than large protein deposits, might be mostly implicated in neuronal damage. Several strategies are being pursued to inhibit and/or reverse protein misfolding and aggregation, with the hope that some of them will result in the generation of drugs that will be useful for the treatment of neurodegenerative diseases. Additional research is necessary to demonstrate definitively the involvement of protein misfolding and aggregation as a common cause of neurodegenerative diseases. Future work should also focus on understanding the contribution of alternative protein folding in other diseases and in normal cellular functioning.

Journal

Nature Reviews Neuroscience – Springer Journals

Published: Jan 1, 2003

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