Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD.
FTD
GRN
PGRN
TDP-43
granulin
lysosome
microglia
myelin
progranulin
white matter
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
24 08 2021
24 08 2021
Historique:
received:
14
12
2020
revised:
07
06
2021
accepted:
29
07
2021
entrez:
25
8
2021
pubmed:
26
8
2021
medline:
12
2
2022
Statut:
ppublish
Résumé
Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology.
Identifiants
pubmed: 34433069
pii: S2211-1247(21)01015-9
doi: 10.1016/j.celrep.2021.109581
pmc: PMC8491969
mid: NIHMS1735791
pii:
doi:
Substances chimiques
GRN protein, human
0
Grn protein, mouse
0
Progranulins
0
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
109581Subventions
Organisme : NINDS NIH HHS
ID : P01 NS084974
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097273
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS120992
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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