Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination

PNAS, 2018 · DOI: 10.1073/pnas.1809821115 · Published: October 29, 2018

Simple Explanation

TDP-43 aggregates are a hallmark of ALS and FTD. This study investigates the normal function of TDP-43 in oligodendrocytes, brain cells responsible for myelination. The researchers found that TDP-43 is essential for the survival and function of oligodendrocytes. Specifically, it's needed for myelination, the process of forming a protective sheath around nerve fibers. Loss of TDP-43 in oligodendrocytes leads to their degeneration and reduced myelination. Interestingly, while some oligodendrocytes die, others proliferate in an attempt to compensate for the loss.

Study Duration

Not specified

Participants

Mice with TDP-43 deleted in mature oligodendrocytes

Evidence Level

Level 3: Animal study

Key Findings

1
TDP-43 is indispensable for oligodendrocyte survival and myelination. Deletion leads to progressive neurological phenotypes and early lethality.
2
TDP-43 deletion triggers RIPK1-mediated necroptosis (a form of cell death) of mature oligodendrocytes in both gray and white matter.
3
TDP-43 regulates the expression of myelin-related genes such as Plp1 and Mbp, which are essential for myelination.

Research Summary

This study demonstrates that TDP-43 is essential for the proper function of oligodendrocytes, particularly for myelination and cell survival. Deleting TDP-43 in mature oligodendrocytes leads to their degeneration via RIPK1-mediated necroptosis and a reduction in the expression of myelin proteins. The study also reveals a difference in regeneration capacity between gray and white matter oligodendrocytes upon TDP-43 loss, with white matter showing enhanced proliferation of precursor cells.

Practical Implications

Therapeutic Target Identification

Inhibition of necroptosis could be a potential therapeutic strategy for neurodegenerative diseases involving TDP-43 proteinopathies.

Understanding ALS/FTD Pathogenesis

The findings highlight the contribution of oligodendrocyte dysfunction to the pathogenesis of ALS and FTD, suggesting glial cells as potential therapeutic targets.

Enhancing Oligodendrocyte Function

Boosting oligodendrocyte function may be considered as an additional therapeutic intervention for ALS/FTD, AD, and age-related cognitive decline.

Study Limitations

1
The study was conducted on mice, and the results may not directly translate to humans.
2
The precise mechanisms by which TDP-43 regulates the expression of myelin-related genes require further investigation.
3
The long-term consequences of enhanced oligodendrocyte precursor cell proliferation in the white matter are not fully understood.

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