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Unfolding the role of protein misfolding in neurodegenerative diseases

Key Points

  • 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.


Recent evidence indicates that diverse neurodegenerative diseases might have a common cause and pathological mechanism — the misfolding, aggregation and accumulation of proteins in the brain, resulting in neuronal apoptosis. Studies from different disciplines strongly support this hypothesis and indicate that a common therapy for these devastating disorders might be possible. The aim of this article is to review the literature on the molecular mechanism of protein misfolding and aggregation, its role in neurodegeneration and the potential targets for therapeutic intervention in neurodegenerative diseases. Many questions still need to be answered and future research in this field will result in exciting new discoveries that might impact other areas of biology.

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Figure 1: Cerebral aggregates in neurodegenerative diseases.
Figure 2: Schematic representation of the pathway leading to protein misfolding and aggregation.
Figure 3: Models for the mechanism of neurodegeneration associated with protein misfolding and aggregation.
Figure 4: Models for the neurotoxic mechanism of misfolded aggregates.
Figure 5: Schematic representation of different therapeutic strategies to arrest protein misfolding and aggregation.


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I thank C. Adessi, K. Maundrell, Y. Fezoui and C. Hetz for stimulating discussions of the ideas described in this review. I also appreciate the work of K. Maundrell and J. Delamarter in critically reading and correcting this manuscript and the continuous support of S. Fumero.

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Alzheimer disease

amyotrophic lateral sclerosis

Creutzfeldt–Jakob disease

Gerstmann–Straussler disease

Huntington disease

Parkinson disease

prion-related protein

spinocerebellar ataxia




apolipoprotein A-II

apolipoprotein E









prion protein









Encyclopedia of Life Sciences

Alzheimer disease

amyotrophic lateral sclerosis



Huntington's disease

Parkinson's disease

prion diseases

protein folding in vivo




A family of cellular proteins that mediate the correct folding of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides in folding by inhibiting alternative assembly pathways that produce nonfunctional structures.


The process by which a protein acquires its native tridimensional structure. Under physiological conditions, each protein has a unique stable folded structure, but in conformational disorders the polypeptide chain adopts an alternative structure, associated with the pathogenesis of the disease.


A recently recognized group of diseases in which the key event is the misfolding, aggregation and tissue deposition of a protein.


A general term for a variety of protein aggregates that accumulate as extracellular fibrils of 7–10 nm and have common structural features, including a β-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavins S and T.


Proliferation and ramification of glial cells in response to brain damage.


The brain damage associated with TSE or prion diseases, consisting of extensive vacuolization of neuronal cells.


β-Sheets and α-helices are the two types of prevalent, repetitive secondary structure in folded proteins. β-Sheets are formed of alternating peptide pleated strands linked by hydrogen bonding between the NH and CO groups of the peptide bond. Formation of β-sheets can be stabilized by protein oligomerization or aggregation.


Structures containing several units of a protein organized in a β-pleated sheet conformation.


The process of programmed cell death, characterized by distinctive morphological changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA.


A family of intracellular cysteine endopeptidases that have a key role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartate residues.


 A disturbance in the pro-oxidant–antioxidant balance in favour of the former, leading to potential cellular damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation and lipid peroxidation products.


An inflammatory process involving the brain and meninges, most often produced by pathogenic organisms that invade the central nervous system, and occasionally by toxins, autoimmune disorders and other conditions.

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Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4, 49–60 (2003).

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