Researchers at the University of Lausanne in Switzerland have discovered an unknown role for a protein linked to neurodegenerative diseases, such as amyotrophic lateral sclerosis and some forms of dementia.

The researchers said that this protein helps regulate the function of immune cells within the brain, a finding that may help explain how these cells contribute to brain and motor dysfunction.

The study, published in the journal Nature Neuroscience, found that loss of the protein, known as TDP-43, within microglial cells led to early disturbances in brain structure and the myelin sheath surrounding nerve fibers in mice, later associated with the onset of motor deficits in adulthood.

Brain Immune Cells

Microglial cells, or microglia, the primary immune cells in the central nervous system, act as a first line of defense in the brain, spinal cord, and retina; they not only attack pathogens but also clean up dead cells and tissue debris, helping to regulate the brain environment during and after development.

But in recent years, these same cells have emerged as a potential factor in neurodegenerative diseases, not merely as supporting cells but as players that may alter the course and severity of the disease.

The new study focused on the TDP-43 protein, which is normally found inside the cell nucleus and helps regulate RNA processing.

A Protein That Loses Its Function

In diseases such as amyotrophic lateral sclerosis and frontotemporal dementia, this protein often translocates from the nucleus to the cytoplasm, where it aggregates into abnormal clumps.

The researchers believe the problem is not limited to the toxicity of these clumps but also includes the loss of the protein's normal function within the nucleus.

Co-author Rosa Chiara Paolicelli said the study aimed to understand what happens when TDP-43 loses its function specifically in microglia, not just in neurons. To achieve this, researchers deleted the protein's gene in microglial cells of experimental mice.

Mice that lost TDP-43 in microglia during early life showed motor impairments in adulthood.

Using magnetic resonance imaging, confocal microscopy, and electron microscopy, researchers observed structural changes in specific brain regions, as well as defects in myelin, the insulating sheath surrounding nerve fibers that helps efficiently transmit signals.

Co-author Anne-Claire Compagnon said researchers also noted molecular changes indicating dysfunction in oligodendrocytes, the cells responsible for producing myelin.

This finding suggests that microglial disruption may affect other cells in the brain, upsetting the delicate balance required for nerve fiber growth and maintenance.

The study found that microglia lacking TDP-43 lose part of their ability to engulf and digest myelin defects that naturally occur during brain development. Instead of helping refine the nerve sheath and clean up structural errors, these cells become less efficient, allowing disorders to accumulate that may have long-term effects.

Gene Confusion

At the molecular level, researchers linked this defect to a pathway known as TREM2-DAP12, a key route for microglial functions.

The researchers found that loss of TDP-43 disrupted the function of a gene within the cell, resulting in an incomplete protein that weakened important signals required for brain immune cells to function normally.

This may explain how the loss of this protein impairs microglial cells' ability to handle myelin problems, the sheath that protects nerve fibers and helps them transmit signals efficiently, according to the study.

The significance of the findings is that they shift some of the scientific attention on TDP-43 away from neurons alone to immune cells in the brain. Previous studies often focused on the accumulation of this protein within neurons in diseases like ALS and dementia, whereas the new results suggest that microglial dysfunction may be sufficient, under certain conditions, to cause long-term changes in the brain and motor behavior.

The study reveals a previously unknown role for TDP-43 in regulating microglial function and demonstrates how disruption of this function can contribute to the development of neurological disorders.