Unexpected Findings May Help Explain Start of Rare Neurodegenerative Disease

Recent research led by scientists at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases is helping build a better understanding of iron accumulation in the brains of people with progressive supranuclear palsy (PSP).

The research, published in the Annals of Neurology, helps explain how the disease begins and lays the groundwork for future research to improve treatment.

“In this paper, we introduced novel aspects of PSP, and having studied the regions of the brain that are affected early, we think this work may give some insight into the cause of PSP,” says Seojin Lee, the first author on the paper.

Lee is a PhD student in the lab of Gabor Kovacs, who is a professor in the department of laboratory medicine and pathobiology at U of T’s Temerty Faculty of Medicine, investigator at the Tanz Centre, consultant at University Health Network and senior scientist at Krembil Brain Institute.

Progressive supranuclear palsy is a neurodegenerative disorder that impairs balance, speech and vision. In brains affected by PSP and other neurodegenerative diseases, a protein called tau accumulates in specific areas starting in the globus pallidus and substantia nigra, which are involved in movement and other functions. Those same regions also accumulate iron during normal aging.

Tau and iron seem to be tightly linked in neurodegenerative diseases; previous research suggests that the tau protein has a role in moving iron out of cells, while iron seems to promote tau aggregation in cells.

Lee wanted to examine iron accumulation in PSP and whether it is involved in initiating the disease. She had also noticed a significant gap in the scientific literature about PSP — no research had been done to determine which brain cells accumulate iron.

Lee and the research team, which included researchers at the Tanz Centre as well as collaborators in Spain, therefore examined samples of brains from people who had PSP and compared them to non-diseased brains. They also looked at which cells accumulate iron and studied the expression of genes that help maintain the balance of iron and oxygen in brain cells, a process known as homeostasis.

“Each type of brain cell handles iron differently, so iron accumulation is most likely not going to be uniform across all brain cell types,” says Lee. “Figuring out which cell type accumulates more iron than the others is the critical first step in figuring out the role of iron in the cause of this disease. If we find out the key cell type where the iron is accumulating, we can focus our research on that cell type.”

To do this, the team developed a new staining method that combines staining for iron deposits with immunohistochemistry, to identify cell types with iron deposition. They found that iron accumulated most in astrocytes, which have many functions including regulation of blood flow and provision of nutrients to neurons. They found that these same cells accumulate the tau protein. Moreover, they found neurons in the same regions show dysregulated oxygen homeostasis.

Finally, the team examined the genes involved in oxygen and iron homeostasis to better understand the mechanisms involved. To their surprise, they found gene dysregulation in PSP similar to what is seen in a group of disorders called Neurodegeneration with Brain Iron Accumulation (NBIA). These diseases are characterized by iron accumulation in the brain that is much higher than what is found in other neurodegenerative diseases.

“This was totally unexpected, but we were really excited about this discovery,” says Lee. “It suggests that these genes that are involved in NBIA might also be involved in PSP, which is a novel finding that may stir a new way of thinking about PSP disease pathways.”

The discovery that the same genes could be involved in both NBIA and PSP, especially as both diseases can accompany tau pathology in the affected brains, suggests one possibility of how the disease progresses in the early stages.

Lee is now building on these findings with experimental studies to confirm these results. Ultimately, she hopes the results can be used to improve therapies for patients with this rare condition.

“It’s still early days, but hopefully this work has some impact to improve the iron accumulation therapies that are used in these patients,” she says. “This study opens many doors into what we can explore.”