Pathogenic variants of Valosin-containing protein induce lysosomal damage and transcriptional activation of autophagy regulators in neuronal cells.
ALS
PQC
TFE3
lysosome
neurodegeneration
p97
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
14
04
2022
received:
09
10
2021
accepted:
28
04
2022
pubmed:
3
5
2022
medline:
8
7
2022
entrez:
2
5
2022
Statut:
ppublish
Résumé
Mutations in the valosin-containing protein (VCP) gene cause various lethal proteinopathies that mainly include inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). Different pathological mechanisms have been proposed. Here, we define the impact of VCP mutants on lysosomes and how cellular homeostasis is restored by inducing autophagy in the presence of lysosomal damage. By electron microscopy, we studied lysosomal morphology in VCP animal and motoneuronal models. With the use of western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and filter trap assay, we evaluated the effect of selected VCP mutants in neuronal cells on lysosome size and activity, lysosomal membrane permeabilization and their impact on autophagy. We found that VCP mutants induce the formation of aberrant multilamellar organelles in VCP animal and cell models similar to those found in patients with VCP mutations or with lysosomal storage disorders. In neuronal cells, we found altered lysosomal activity characterised by membrane permeabilization with galectin-3 redistribution and activation of PPP3CB. This selectively activated the autophagy/lysosomal transcriptional regulator TFE3, but not TFEB, and enhanced both SQSTM1/p62 and lipidated MAP1LC3B levels inducing autophagy. Moreover, we found that wild type VCP, but not the mutants, counteracted lysosomal damage induced either by trehalose or by a mutant form of SOD1 (G93A), also blocking the formation of its insoluble intracellular aggregates. Thus, chronic activation of autophagy might fuel the formation of multilamellar bodies. Together, our findings provide insights into the pathogenesis of VCP-related diseases, by proposing a novel mechanism of multilamellar body formation induced by VCP mutants that involves lysosomal damage and induction of lysophagy.
Identifiants
pubmed: 35501124
doi: 10.1111/nan.12818
pmc: PMC10588520
mid: NIHMS1862639
doi:
Substances chimiques
Cell Cycle Proteins
0
Adenosine Triphosphatases
EC 3.6.1.-
Valosin Containing Protein
EC 3.6.4.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12818Subventions
Organisme : NIAMS NIH HHS
ID : R56 AR050236
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR063360
Pays : United States
Organisme : NIAMS NIH HHS
ID : R03 AR050161
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR050236
Pays : United States
Organisme : NIAMS NIH HHS
ID : R56 AR066970
Pays : United States
Informations de copyright
© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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