Heat shock proteins in neurodegenerative disorders and aging

Abstract

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer’s and Parkinson’s disease.

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Fig. 1

Abbreviations

ARE:

Antioxidant response element

AIF:

Apoptosis-inducing factor

Apaf1:

Apoptotic protease activation factor 1

Ask1:

Apoptosis signal-regulating kinase

ATF6:

Activating transcription factor 6

BAG-1:

Bcl-2-associated athanogene

CHIP:

Carboxy terminus of Hsp70-interacting protein

CHOP:

CCAAT-enhancer-binding protein homologous protein

JNK:

c-Jun N-terminal kinase

ERAD:

Endoplasmic reticulum-associated protein degradation

GRP:

Glucose-regulated protein

Hsc70:

Heat shock cognate 70

Hsp:

Heat shock protein

HO1:

Heme oxygenase 1

Hip:

Hsp70-interacting protein

Hop:

Hsp70/90-organizing protein

Keap1:

Kelch-like ECH-associated protein 1

LRRK2:

Leucine-rich repeat kinase 2

LAMP2a:

Lysosomal-associated membrane transporter 2a

mtHsp70:

Mitochondrial Hsp70

Nrf2:

Nuclear factor erythroid 2 related factor 2

PERK:

PRKR-like endoplasmic reticulum kinase

IRE1:

Serine/threonine-protein kinase/endoribonuclease

TPR1:

Tetratrico-peptide repeat-1

TRAP1:

TNF receptor-associated protein 1

UPR:

Unfolded protein response

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Acknowledgments

We apologize that we were not able to include all the many references on heat shock protein expression in the brain. RKL has no conflicts to declare. We are grateful to Mary Caruso, Deb Willson, and Jackie Farrer for outstanding administrative support.

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Correspondence to Rehana K. Leak.

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Leak, R.K. Heat shock proteins in neurodegenerative disorders and aging. J. Cell Commun. Signal. 8, 293–310 (2014). https://doi.org/10.1007/s12079-014-0243-9

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Keywords

  • Chaperone
  • Vitagene
  • Proteostasis
  • Ageing
  • Aging
  • Adaptation
  • Hormesis