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Molecular Neurobiology

, Volume 53, Issue 2, pp 905–931 | Cite as

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

  • Yanuar Alan Sulistio
  • Klaus HeeseEmail author
Article

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.

Keywords

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

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

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

Notes

Acknowledgments

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

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Graduate School of Biomedical Science and EngineeringHanyang UniversitySeongdong-guRepublic of Korea

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