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

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Cholesterol metabolism is crucial for the central nervous system (CNS), with most cholesterol found in myelin.
• TDP-43 protein is a key pathological marker in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Purpose of the Study:

• To investigate the role of TDP-43 in regulating cholesterol metabolism within oligodendrocytes.
• To explore the link between TDP-43, cholesterol dysmetabolism, and neurodegenerative diseases like ALS and FTD.

Main Methods:

• Investigated TDP-43 binding to mRNAs involved in cholesterol metabolism (SREBF2, HMGCR, HMGCS1, LDLR).
• Assessed effects of TDP-43 depletion on cholesterol levels in vitro and in vivo.
• Utilized reintroduction of SREBF2 or LDLR, and cholesterol supplementation to rescue TDP-43-related phenotypes.
• Examined oligodendrocytes from FTD patients for TDP-43 pathology and cholesterol-related protein expression.

Main Results:

• TDP-43 directly binds to mRNAs regulating cholesterol biosynthesis and uptake.
• TDP-43 depletion reduces SREBF2 and LDLR expression, leading to lower cholesterol levels.
• Restoring SREBF2/LDLR or supplementing cholesterol rescues demyelination caused by TDP-43 deletion.
• FTD patient oligodendrocytes show altered cholesterol metabolism markers and TDP-43/LDLR coaggregation.

Conclusions:

• TDP-43 plays a significant role in maintaining cholesterol homeostasis in oligodendrocytes.
• Cholesterol dysmetabolism is implicated in the pathogenesis of TDP-43 proteinopathies, suggesting potential therapeutic targets.