Pathologic TDP-43 downregulates myelin gene expression in the monkey brain
Longhong Zhu1, Dazhang Bai1,2, Xiang Wang1
1Guangdong Key Laboratory of Non-human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
Brain Pathology (Zurich, Switzerland)
|May 23, 2024
Summary
Truncated TDP-43 fragments in oligodendrocytes cause myelin damage in ALS. This TDP-35 accumulation disrupts myelin gene expression, impacting axonal integrity and disease progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Oligodendrocytes, non-neuronal cells, are crucial for axonal integrity and implicated in Amyotrophic Lateral Sclerosis (ALS).
- Cytoplasmic accumulation of TDP-43 in oligodendrocytes is a pathological hallmark in neurodegenerative diseases, but its functional impact remains unclear.
- Primate-specific cleavage of TDP-43 into truncated fragments has been observed in neural cells, suggesting a potential role in disease pathogenesis.
Purpose of the Study:
- To investigate the specific role of truncated TDP-43, particularly TDP-35, in oligodendrocytes on myelin structure.
- To elucidate the mechanism by which TDP-35 accumulation affects myelin integrity and gene expression.
- To provide insights into the gain-of-function mechanisms of TDP-43 in oligodendrocytes relevant to ALS and other neurodegenerative diseases.
Main Methods:
- Utilized a monkey model to study the effects of truncated TDP-35 specifically in oligodendrocytes.
- Analyzed myelin structure in the corpus callosum.
- Investigated the interaction between TDP-35 and myelin regulatory factor.
- Assessed the transcriptional regulation of myelin-associated genes.
Main Results:
- Truncated TDP-35 specifically in oligodendrocytes induced dysfunctional demyelination in the monkey corpus callosum.
- Accumulation of TDP-35 in the cytoplasm led to an interaction with myelin regulatory factor.
- This interaction resulted in the downregulation of downstream myelin-associated genes at the transcriptional level.
Conclusions:
- Truncated TDP-43, specifically TDP-35, in oligodendrocytes contributes to myelin structure injury.
- The interaction between cytoplasmic TDP-35 and myelin regulatory factor disrupts myelin gene expression, offering a gain-of-function mechanism in TDP-43 related diseases.
- These findings enhance understanding of oligodendrocyte dysfunction in the pathogenesis of ALS and related neurodegenerative conditions.
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