Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer’s disease

Francesca Natale, Matteo Spinelli, Marco Rinaudo, Walter Gulisano, Ida Nifo Sarrapochiello, Giuseppe Aceto, Daniela Puzzo, Salvatore Fusco, Claudio Grassi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Protein post-translational modifications (PTM) play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer’s disease (AD) patients. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Aβ deposition in the hippocampus and extended the lifespan of both male and female 3×Tg-AD mice. Moreover, hippocampal silencing of zDHHC7 prevented the onset of cognitive deficits in the same experimental model. We also identified a FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression, which was triggered by brain insulin resistance in 3×Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with Aβ 1 to 42 load and they inversely correlated with Mini Mental State Examination scores. Our data reveal a key role of both zDHHC7 overexpression and protein hyperpalmitoylation in the onset and progression of AD-related alterations of synaptic plasticity and memory.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaProceedings of the National Academy of Sciences of the United States of America
Volume121
DOI
Stato di pubblicazionePubblicato - 2024

Keywords

  • Alzheimer’s disease
  • BACE1
  • zDHHC
  • protein S-palmitoylation
  • brain insulin resistance

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