The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Abstract

One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer’s disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.

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Abbreviations

aa:

Amino acid

AD:

Alzheimer’s disease

ADAM:

A disintegrin and metalloproteinase

AFT:

AICD-FE65-TIP60

AICD:

APP intracellular c-terminal domain

ALS:

Amyotrophic lateral sclerosis

AMPK:

AMP-activated kinase

AP:

Amyloid plaque

APH1:

Anterior pharynx-defective 1

APOE4:

Apolipoprotein E4

APP:

Amyloid precursor protein

Aβ:

Amyloid-beta peptide

BACE1:

Beta-site APP cleaving enzyme 1

CaMK:

Calcium/calmodulin-dependent protein kinase II

CDK5:

Cyclin-dependent kinase 5

CHIP:

Carboxyl terminus of HSP70-interacting protein

chr:

Chromosome

CJD:

Creutzfeldt-Jakob disease

CKII:

Casein kinase II

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CUBD:

Cu(II)-binding domain

DLB:

Dementia with Lewy bodies

Dyrk1A:

Dual-specificity tyrosine-regulated kinase 1A

EGFR:

Epidermal growth factor receptor

EOAD:

Early-onset AD

ER:

Endoplasmic reticulum

FKBD:

FK506-binding domain

FKBP:

FK506-binding protein

FTDP-17:

Frontotemporal dementia related to chr 17

HBD:

Heparin-binding domain

HD:

Huntington’s disease

HSP:

Heat shock protein

IDP:

Intrinsically disordered protein

KPI:

Kunitz-type serine protease inhibitor

LOAD:

Late-onset AD

LRP1:

Lipoprotein receptor-related protein 1

LTP:

Long-term potentiation

MAP:

Microtubule-associated protein

MAPK:

Mitogen-activated protein kinase

MAPT:

Microtubule-associated protein Tau

MARK:

MAP/microtubule-affinity-regulating kinases

MRI:

Magnetic resonance imaging

NFT:

Neurofibrillary tangle

NICD:

Notch intracellular domain

NPC:

Neural precursor cell

PD:

Parkinson’s disease

PEN2:

Presenilin enhancer 2

PHF:

Paired helical filament

PIN1:

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1

PKA:

Protein kinase A

PKC:

Protein kinase C

PrP:

Prion protein

PS1/2:

Presenilin-1/Presenilin-2

RIP:

Regulated intramembrane proteolysis

RTN:

Reticulon family protein

SOD1:

Superoxide dismutase 1

SVZ:

Subventricular zone

TACE:

Tumor necrosis factor-α converting enzyme

TAG1:

Transient axonal glycoprotein

TAI:

Tau aggregation inhibitor

TDP-43:

TAR DNA-binding protein-43

TGN:

Trans-Golgi network

TRIM:

Tripartite motif

UBB:

Ubiquitin B

UBC:

Ubiquitin C

UPS:

Ubiquitin-proteasome system

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Acknowledgments

This work was supported by the research fund of Hanyang University.

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The authors declare that they have no conflict of interest.

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Correspondence to Klaus Heese.

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Sulistio, Y.A., Heese, K. The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease. Mol Neurobiol 53, 905–931 (2016). https://doi.org/10.1007/s12035-014-9063-4

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Keywords

  • Alzheimer’s disease
  • Ubiquitin-proteasome system
  • Amyloid-beta
  • Tau protein
  • FKBP
  • Prion-like transmission