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TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination.
- Source :
-
The Journal of cell biology [J Cell Biol] 2021 Sep 06; Vol. 220 (9). Date of Electronic Publication: 2021 Aug 04. - Publication Year :
- 2021
-
Abstract
- Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43-mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies-related diseases.<br /> (© 2021 Ho et al.)
- Subjects :
- Animals
DNA-Binding Proteins deficiency
Disease Models, Animal
Female
Frontal Lobe metabolism
Frontal Lobe pathology
Frontotemporal Dementia metabolism
Frontotemporal Dementia pathology
Gene Expression Profiling
Gene Expression Regulation
Humans
Hydroxymethylglutaryl-CoA Synthase genetics
Hydroxymethylglutaryl-CoA Synthase metabolism
Lipid Metabolism genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin Sheath pathology
Oligodendroglia pathology
Organoids metabolism
Organoids pathology
Primary Cell Culture
Receptors, LDL genetics
Receptors, LDL metabolism
Signal Transduction
Spinal Cord metabolism
Spinal Cord pathology
Sterol Regulatory Element Binding Protein 2 metabolism
Temporal Lobe metabolism
Temporal Lobe pathology
Cholesterol metabolism
DNA-Binding Proteins genetics
Frontotemporal Dementia genetics
Myelin Sheath metabolism
Oligodendroglia metabolism
Sterol Regulatory Element Binding Protein 2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8140
- Volume :
- 220
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 34347016
- Full Text :
- https://doi.org/10.1083/jcb.201910213