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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This work was supported by the research fund of Hanyang University.
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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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DOI: https://doi.org/10.1007/s12035-014-9063-4