TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
20 Nov 2023
20 Nov 2023
Historique:
received:
05
02
2023
accepted:
13
10
2023
pubmed:
21
11
2023
medline:
21
11
2023
entrez:
21
11
2023
Statut:
aheadofprint
Résumé
Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome-immune relationship, we specifically disrupted the TFEB-v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB-v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer's disease.
Identifiants
pubmed: 37985800
doi: 10.1038/s41593-023-01494-2
pii: 10.1038/s41593-023-01494-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : NS093652
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : AG066606
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : AG020670
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : AG062257
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : AG062746
Organisme : Cure Alzheimer's Fund (Alzheimer's Disease Research Foundation)
ID : NA
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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