title: 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.
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
authors.forename: Yanuar Alan
authors.initials: YA
authors.lastname: Sulistio
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea. klaus@hanyang.ac.kr.
authors.forename: Klaus
authors.initials: K
authors.lastname: Heese
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer’s disease; Amyloid-beta; FKBP; Prion-like transmission; Tau protein; Ubiquitin-proteasome system