Melatonin directly binds and inhibits death-associated protein kinase 1 function in Alzheimer's disease.
Alzheimer's disease
Pin1
death-associated protein kinase 1 (DAPK1)
melatonin
tau
Journal
Journal of pineal research
ISSN: 1600-079X
Titre abrégé: J Pineal Res
Pays: England
ID NLM: 8504412
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
16
12
2019
revised:
02
04
2020
accepted:
24
04
2020
pubmed:
3
5
2020
medline:
30
11
2021
entrez:
3
5
2020
Statut:
ppublish
Résumé
Death-associated protein kinase 1 (DAPK1) is upregulated in the brains of human Alzheimer's disease (AD) patients compared with normal subjects, and aberrant DAPK1 regulation is implicated in the development of AD. However, little is known about whether and how DAPK1 function is regulated in AD. Here, we identified melatonin as a critical regulator of DAPK1 levels and function. Melatonin significantly decreases DAPK1 expression in a post-transcriptional manner in neuronal cell lines and mouse primary cortical neurons. Moreover, melatonin directly binds to DAPK1 and promotes its ubiquitination, resulting in increased DAPK1 protein degradation through a proteasome-dependent pathway. Furthermore, in tau-overexpressing mouse brain slices, melatonin treatment and the inhibition of DAPK1 kinase activity synergistically decrease tau phosphorylation at multiple sites related to AD. In addition, melatonin and DAPK1 inhibitor dramatically accelerate neurite outgrowth and increase the assembly of microtubules. Mechanistically, melatonin-mediated DAPK1 degradation increases the activity of Pin1, a prolyl isomerase known to play a protective role against tau hyperphosphorylation and tau-related pathologies. Finally, elevated DAPK1 expression shows a strong correlation with the decrease in melatonin levels in human AD brains. Combined, these results suggest that DAPK1 regulation by melatonin is a novel mechanism that controls tau phosphorylation and function and offers new therapeutic options for treating human AD.
Identifiants
pubmed: 32358852
doi: 10.1111/jpi.12665
pmc: PMC7890046
mid: NIHMS1600182
doi:
Substances chimiques
DAPK1 protein, human
EC 2.7.11.1
Dapk1 protein, mouse
EC 2.7.11.1
Death-Associated Protein Kinases
EC 2.7.11.1
Melatonin
JL5DK93RCL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12665Subventions
Organisme : Natural Science Foundation of Fujian Province
ID : 2019J05072
Organisme : Alzheimer's Association
ID : AARG-17-528817
Pays : United States
Organisme : Natural Science Foundation of Fujian Province
ID : 2019J01297
Organisme : Fujian Medical University
ID : XRCZX2017007
Organisme : National Natural Science Foundation of China
ID : 81970993
Organisme : Medical Innovation Grant of Fujian Province
ID : 2019-CX-36
Organisme : NIA NIH HHS
ID : R01 AG046319
Pays : United States
Organisme : National Natural Science Foundation of China
ID : 81901071
Organisme : NIA NIH HHS
ID : R01 AG055559
Pays : United States
Organisme : Fujian Medical University
ID : XRCZX2017019
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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