TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

• Published in: The Journal of cell biology Vol. 220; no. 9; p. 1
• Main Authors: Ho, Wan Yun, Chang, Jer-Cherng, Lim, Kenneth, Cazenave-Gassiot, Amaury, Nguyen, Aivi T., Foo, Juat Chin, Muralidharan, Sneha, Viera-Ortiz, Ashley, Ong, Sarah J.M., Hor, Jin Hui, Agrawal, Ira, Hoon, Shawn, Arogundade, Olubankole Aladesuyi, Rodriguez, Maria J., Lim, Su Min, Kim, Seung Hyun, Ravits, John, Ng, Shi-Yan, Wenk, Markus R., Lee, Edward B., Tucker-Kellogg, Greg, Ling, Shuo-Chien
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06.09.2021
• Subjects: Amyotrophic lateral sclerosis; Animals; Biosynthesis; Central nervous system; Cholesterol; Cholesterol - metabolism; Dementia disorders; Demyelination; Depletion; Disease Models, Animal; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Female; Frontal Lobe - metabolism; Frontal Lobe - pathology; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Synthase - genetics; Hydroxymethylglutaryl-CoA Synthase - metabolism; Lipid metabolism; Lipid Metabolism - genetics; Male; Membrane and lipid biology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelination; Neuroscience; Oligodendrocytes; Oligodendroglia - metabolism; Oligodendroglia - pathology; Organoids - metabolism; Organoids - pathology; Physiology; Primary Cell Culture; Proteins; Receptors, LDL - genetics; Receptors, LDL - metabolism; RNA biology; Signal Transduction; Spinal Cord - metabolism; Spinal Cord - pathology; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; Supplements; Temporal Lobe - metabolism; Temporal Lobe - pathology; Transcription
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.201910213

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.