Familial Dysautonomia: Insights from Mouse Model Research

Familial Dysautonomia (FD) is a genetic disorder that affects the nervous system. It is also known as Riley-Day syndrome. This condition affects both the sensory (which includes how we feel things) and autonomic nervous systems (which controls automatic body functions like breathing and heart rate). People with FD can have serious problems with regulating temperature, feeling pain, and controlling heart rate.

#Symptoms of Familial Dysautonomia

The main symptoms of FD include:

• Insensitivity to pain and temperature, meaning patients may not feel when they are hurt or too hot or cold.
• Difficulty crying, which may appear as a lack of tears.
• Problems with the heart, such as irregular heartbeats.
• Issues with vision, particularly with the retina, which may lead to eyesight problems.
• Progressive ataxia, which refers to problems with coordination and balance.

Sadly, many people with this condition do not live beyond the age of 40.

#Genetic Causes of Familial Dysautonomia

FD is caused by a specific genetic change in the ELP1 gene. This gene is responsible for producing a protein important for certain cellular processes in the nervous system. A mutation in this gene leads to a reduction of the ELP1 protein, especially in nerve cells.

#The Role of the Cerebellum

The cerebellum is a part of the brain that plays a key role in coordinating movement and balance. Researchers found that the ELP1 gene is more commonly mis-spliced in the cerebellum than in other body areas, suggesting that low levels of ELP1 protein in this part of the brain may contribute to coordination problems in FD patients.

#Investigating Elp1’s Function in the Cerebellum

To understand how the loss of ELP1 affects balance and coordination, researchers created a specially modified mouse model where ELP1 was removed from certain brain cells called granule cell progenitors. These mice began to show signs of ataxia, or balance problems, at just eight weeks old.

Although the overall structure of their cerebellum appeared normal under a microscope, these mice had fewer Granule Cells, which are critical for proper cerebellar function. At a young age, they exhibited fewer mature granule cells and shorter dendrites in Purkinje cells, another type of brain cell. The loss of ELP1 seemed to lead to increased cell death in developing granule cells.

#ELP1 Levels in Granule Cell Progenitors

Previous research showed that ELP1 is most abundant in early cerebellar development and remains high in granule cells during growth. To assess how ELP1 levels changed throughout development, scientists looked at different stages and cell types in both humans and mice. They discovered that while ELP1 expression increased in human cerebellar cells, mouse cells showed a decrease after birth.

Despite these differences, ELP1 was still highly expressed in granule cells in both species. This suggests that ELP1 is crucial for the health of these cells throughout development.

#Cell Proliferation and ELP1 Expression

Further experiments revealed that granule cell progenitors express high levels of ELP1 while they are still dividing and growing. Researchers confirmed that when these cells were encouraged to grow in a lab setting using a specific growth factor, they maintained higher levels of ELP1 protein. Upon differentiation into mature granule cells, ELP1 levels dropped.

By creating a mouse model that specifically knocked out ELP1 in granule cell progenitors, researchers found a marked decrease in ELP1 levels in these cells but not in Purkinje cells. This suggests that ELP1 is critical for granule cells, but its absence does not significantly affect other cell types in the cerebellum.

#Behavioral Changes in Elp1 Knockout Mice

Mice that had ELP1 removed from their granule cells showed clear signs of ataxia, which became apparent as they aged. The animals displayed an unsteady gait similar to that seen in other mouse models for ataxia. Researchers carefully monitored their health and motor skills using various tests that measured movement, strength, and balance.

These tests indicated that as the mice aged, their motor function worsened. By the time they were twelve weeks old, the Elp1 knockout mice exhibited significant deficits in motor performance compared to their control counterparts.

#Structural Changes in the Cerebellum

Upon examining the brains of the older knockout mice, scientists observed that their cerebella were smaller and contained fewer granule cells than those of control mice. This decrease in size likely resulted from the earlier loss of granule cells, as the area of the cerebellum responsible for these cells was significantly reduced.

Despite these differences, the total number of Purkinje cells remained unchanged, although their dendrites were shorter. The reduced connection between granule cells and Purkinje cells could explain the motor coordination issues observed in these mice.

#Early Developmental Changes in Elp1 Knockout Mice

Researchers also looked at the mice at an earlier age, just after the birth stage. They found that even as young as seven days old, the knockout mice exhibited a slight decrease in cerebellum size and weight. While the overall numbers of granule cell progenitors did not significantly change, there were fewer mature granule cells compared to the control mice.

This indicates that the problems in coordination associated with ELP1 loss may begin much earlier in development.

#Molecular Mechanisms Behind Ataxia

At the molecular level, scientists explored the changes in gene expression caused by the loss of ELP1. They found that several genes tied to stress response, cell cycle control, and apoptosis (programmed cell death) were significantly affected. The transcriptional profile revealed that the loss of ELP1 led to increased expression of genes that inhibit cell cycle activity and enhance apoptosis.

These findings point to an increase in stress within the granule cell progenitors, leading to more cell deaths. This increased cell death likely explains the reduced number of mature granule cells and ultimately contributes to the development of ataxia.

#Similarities to Human Conditions

The findings in the mouse model draw parallels to the symptoms seen in FD patients. People with FD often have difficulties with balance and coordination that worsen over time. While the exact mechanisms in humans may differ, the role of ELP1 in maintaining the health of granule cells in the cerebellum may be relevant to understanding why coordination issues arise in these patients.

#Conclusion

Overall, the study shows that ELP1 plays a vital role in the health and function of granule cells within the cerebellum. The loss of ELP1 leads to reduced granule cell populations and increased cell death, resulting in significant motor coordination issues. Understanding these mechanisms could provide insights into potential therapeutic approaches for conditions like Familial Dysautonomia and associated Ataxias. Further research is needed to explore how these findings translate to human health and the potential for interventions that could improve patient outcomes.