Dr. Young Ah Seo from the University of Michigan
Dr. Young Ah Seo’s recently completed research, “Defining the Roles of Iron in BPAN,” has generated new information about how iron accumulates in the brains of individuals with Beta-propeller Protein-associated Neurodegeneration (BPAN), the most common form of NBIA.
Seo, an assistant professor in the department of nutritional sciences at the University of Michigan School of Public Health in Ann Arbor, and her team, observed that the dysfunctional WDR45 gene in BPAN led to impaired iron storage in the brain, causing iron to build up to a toxic level that damages cells.
In 2018, Seo received the first-ever early-career research grant from the NBIA Disorders Association, for $150,000. Although the grant work was meant to be completed in two years, Seo received a one year, no-cost extension because of delays caused by the pandemic.
Her team’s goal was to identify the major proteins and pathways involved in iron accumulation when the WDR45 gene is deficient and how the altered iron uptake and metabolism contribute to neurodegeneration.
The WDR45 gene is involved in autophagy, a natural process that helps clear unnecessary materials from cells. Exactly how the mutated gene also leads to iron accumulation in the brain has not yet been fully understood, so Seo and her team sought to unravel the mystery.
They successfully generated a cell model of BPAN in which the WDR45 gene was deleted. They saw significantly elevated iron levels in this model, suggesting that it accurately mimicked the condition seen in individuals with BPAN.
They found that the absence of the gene’s protein, also named WDR45 (when not italicized it refers to the protein), led to significant changes in the pathways that are responsible for the uptake and regulation of iron in cells. This may be the basis of brain iron accumulation.
They also observed that the overload of iron in cells in this model was associated with impaired ferritinophagy. This is a form of autophagy that degrades a protein responsible for iron storage in cells, called ferritin. Essentially, the process that helps prevent excessive iron storage was impaired.
Finally, they observed that WDR45 deficiency led to excessive iron accumulation in the mitochondria, altered mitochondria metabolism and overproduction of toxic reactive oxygen species (unstable molecules that easily react and cause cell damage). This may contribute to the neurodegeneration seen with BPAN.
All together, these findings suggest a potential underlying cause of disease to explain how iron accumulates in BPAN.
Seo’s work from this grant has been published in the Journal of Neurochemistry, titled “A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation”. She intends to seek new funding to expand on the project’s findings.