2. Academic Validation
  3. The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice

The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice

  • Neurobiol Dis. 2023 Jul 11;184:106225. doi: 10.1016/j.nbd.2023.106225.
Marc Espina 1,  Nadia Di Franco 1,  Martina Brañas-Navarro 2,  Irene Rodriguez Navarro 1,  Veronica Brito 1,  Laura Lopez-Molina 1,  Carlos Costas-Insua 3,  Manuel Guzmán 3,  Silvia Ginés 4
Affiliations

Affiliations

  • 1 Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid 28031, Spain.
  • 2 Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
  • 3 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid 28031, Spain; Instituto Universitario de Investigación Neuroquímica (IUIN), Universidad Complutense, Madrid 28040, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid 28034, Spain.
  • 4 Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid 28031, Spain. Electronic address: silviagines@ub.edu.
PMID: 37442396 DOI: 10.1016/j.nbd.2023.106225
Abstract

Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant Huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention.

Keywords

ER stress; Huntington's disease; Memory; PERK; Therapeutics; hippocampus.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z