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  • Review Article
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Modulation of neurodegeneration by molecular chaperones

Key Points

  • Molecular chaperones regulate several diverse cellular processes, including protein folding, targeting, transport, degradation and signal transduction. Under conditions of stress, molecular chaperones assist in protein refolding and suppress aggregation, which promotes the maintenance of cellular homeostasis.

  • Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and polyglutamine diseases are characterized by the accumulation of distinct aggregated proteins that are unrelated in their primary amino acid sequence. However, each disease protein has the propensity to form amyloid-like fibrils, a prominent component of the lesions that are characteristic of each disease.

  • One of the main controversies in neurodegenerative disorders is whether the fibrillar state of aggregated disease proteins is protective, inert or pathogenic. Increasing evidence indicates that small, soluble oligomeric forms of disease proteins, rather than the fibrils themselves, might be the most potent neurotoxic species.

  • Several genetic studies in animal models of human disease indicate that molecular chaperones are potent suppressors of neurodegeneration. The mechanism of chaperone protection is not clear, but might, in part, be mediated by attenuation of the formation of soluble, oligomeric forms of disease proteins.

  • Crosstalk between the molecular chaperones and the ubiquitin–proteasome machinery, perhaps mediated by the E3 ligase CHIP (carboxy terminus of heat shock cognate 70-interacting protein), might also be important in the suppression of neurodegeneration by molecular chaperones.

  • Because molecular chaperones function in many diverse cellular processes and compartments, the mechanism by which they provide protection in neurodegenerative diseases is likely to be complex and multifactorial.

  • Treatment of animal models of Parkinson's disease and ALS with small molecules that induce the expression of heat shock proteins is neuroprotective, and might prove to be beneficial to human patients with these disorders.

Abstract

Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.

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Figure 1: Molecular chaperones regulate several important cellular processes.
Figure 2: A general model of amyloid assembly.
Figure 3: Proposed actions of heat shock protein 70 and heat shock protein 40 chaperones on amyloid assembly.
Figure 4: Direct and indirect effects of molecular chaperones on disease protein toxicity.

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Acknowledgements

P.J.M. is supported by the National Institute of Neurological Disorders and Stroke, by a National Institutes of Health construction award, by the Alzheimer's Disease Research Center at the University of Washington and by the Hereditary Disease Foundation under the auspices of the 'Cure Huntington's Disease Initiative'. J.L.W. is funded in part by a Public Health Service National Research Service Award from the National Institute of General Medical Sciences. We thank H. Zareie, H. Fong and M. Sarikaya for assistance with preparation of AFM images.

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DATABASES

Entrez Gene

BAG1

HSC70

HSP40

HSP60

HSP70

HSP90

Hsp104

SOD1

FURTHER INFORMATION

Encyclopedia of Life Sciences

Alzheimer disease

Amyotrophic lateral sclerosis

Huntington disease

Parkinson disease

Glossary

PROTEIN AGGREGATE

An abnormal protein assembly that results from the cohesion of two or more misfolded monomeric proteins. Protein aggregates that form amyloid fibrils are often resistant to solubilization with ionic detergents after boiling.

MOLECULAR CHAPERONES

Several families of highly conserved proteins that mediate the folding or assembly of other proteins, but are not components of the final functional structures. Chaperones target misfolded proteins and prevent protein aggregation in all cell types.

THE UBIQUITIN–PROTEASOME PATHWAY

A major cellular pathway for protein catabolism that is important for the 'housekeeping' and turnover of many regulatory proteins. Degradation by the proteasome occurs by conjugation of multiple ubiquitin moieties to a substrate and degradation of the tagged protein by the 26S proteasome complex. Molecular chaperones cooperate with this pathway to mediate the degradation of misfolded proteins.

LYSOSOME-MEDIATED AUTOPHAGY

An important pathway for intracellular protein degradation that involves an acidic cellular compartment, the lysosome vacuole. This pathway mediates the bulk degradation of cytosol and organelles and might degrade aggregated proteins. Chaperones mediate one form of autophagy.

26S PROTEASOME

A multicatalytic protease that is found in the cytosol, perinuclear regions and nucleus of eukaryotic cells.

AMYLOID FIBRILS

Structures formed by many disease-causing proteins when they aggregate. Amyloid fibrils share common biochemical characteristics such as detergent-insolubility, high β-sheet content and a cross β structure, protease resistance and the ability to bind lipophilic dyes, such as congo red.

INCLUSION BODIES

Cellular structures found inside neurons that are composed of aggregated proteins, including amyloid fibrils, molecular chaperones and components of the ubiquitin–proteaseome pathway. Recent studies indicate that the formation of inclusion bodies correlates with neuronal survival and is a protective response.

ATOMIC FORCE MICROSCOPY

(AFM). A type of scanning probe microscopy, in which a cantilever with a sharp tip scans over a sample, such as an amyloid fibril, on an inorganic surface. The repulsive force between the sample and the tip is transduced into a three-dimensional profile of the sample on the surface.

SPHERICAL AND ANNULAR OLIGOMERS

Metastable structures observed in many amyloid-forming proteins that might be on a pathway to fibril formation. These structures have been proposed to be the principal toxic entities that mediate neuronal dysfunction.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

LIPID RAFTS

Membrane microdomains, formed by high concentrations of sphingolipids and cholesterol immersed in a phospholipid-rich environment, that are involved in specialized pathways of protein/lipid transport and signalling.

GELDANAMYCIN

An ansamycin antibiotic that induces the expression of chaperones. This drug was protective in a fly model of Parkinson's disease.

NUCLEATION

A process by which the addition of a small amount of pre-aggregated protein to a monomeric preparation of the same protein robustly accelerates the assembly of amyloid fibrils.

ON-PATHWAY ASSEMBLY

A misfolded protein monomer or higher-order aggregate that is an obligate intermediate in the formation of amyloid fibrils.

OFF-PATHWAY ASSEMBLY

A misfolded protein monomer or higher-order aggregate that is not an obligate intermedite in the assembly of amyloid fibrils, and might actually compete with on-pathway interactions to suppress amyloid fibril polymerization.

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Muchowski, P., Wacker, J. Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6, 11–22 (2005). https://doi.org/10.1038/nrn1587

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