NBIA NEWS & INFORMATION

Professor Hong Zhang, a researcher at the institute of Biophysics, Chinese Academy of Sciences in Beijing, China, reports findings on his BPAN research. You can also watch a video about his work presented at the recent NBIA scientific symposium that will be available soon.

October 2020

Study sparks new approach to BPAN understanding and treatment

A recently completed BPAN study supported by the NBIA Disorders Association has led to a new understanding of how a genetic flaw causes the disorder and how it could be corrected, lead researcher Dr. Hong Zhang said.

Zhang, a visiting professor at the University of Massachusetts Medical School and a researcher at the Institute of Biophysics, Chinese Academy of Sciences in Beijing, said he was excited by the findings. He and his team are now working on a treatment strategy for BPAN based on the study results, he said.

Zhang’s research received two grants of slightly over $51,000 each in 2017 and 2018 as part of the Million Dollar Bike Ride put on by the Orphan Disease Center at the University of Pennsylvania. NBIA families rode bikes to help raise those funds, which were matched by UPenn. The work has resulted in two publications from the first grant. Zhang will present overall results at the 7th International Symposium on NBIA & Related Disorders which will be virtually from September 30 – October 3, 2020.

Zhang and his team focused on identifying the cause of neuronal damage in Beta-propeller Protein-Associated Neurodegeneration (BPAN) by examining the cell-cleaning process, called autophagy. They found that the process is disrupted because of a mutation in the WDR45 gene and its related protein.

In his research, Zhang generated mouse models with a knockout, or missing Wdr45 gene in the central nervous system. The team also studied a closely related gene, WDR45b, which causes another neurological disease, intellectual disability (ID). These mice performed poorly in learning and memory tests.

Through the study, Zhang and his team made an important observation on the defective autophagy process. In normal cells, an accumulation of waste in the cell is wrapped up in a little sac called an autophagosome. The autophagosome then transports the waste through the cell until it arrives at another sac, called the lysosome. The autophagosome fuses with the lysosome, and the waste is then broken down and recycled.

When Zhang’s team further examined the nerve cells lacking the WDR45 and WDR45b proteins, they noticed that the waste materials were picked up by autophagosomes, but the autophagosomes could not engage with the lysosomes for unloading and recycling. This disruption stopped them from working normally. To solve this problem, the researchers attempted to bypass the point where the disruption occurs. They found that by inhibiting modification of another protein, namely O-GlcNAcyclation of SNAP29, they could reverse the autophagy defects in cells with the WDR45/45B mutation.

Zhang believes this finding points to a promising avenue for treatment.

 

Dr. Young Seo, an assistant professor of nutritional biochemistry at the University of Michigan’s School of Public Health in Ann Arbor, gives an update on her work which will be completed in August 2021.

October 2020

Ongoing BPAN research, funded by the NBIA Disorders Association, is producing new insights into iron accumulation and cell damage in individuals who have Beta-propeller protein-associated neurodegeneration.

BPAN is one of the most common NBIA disorders, which share a common characteristic of iron accumulation in the brain. Researchers are trying to understand what causes the iron to collect in BPAN and its impact on disease symptoms.

In September 2018, the NBIA Disorders Association awarded its first-ever early career grant for $150,000 to Dr. Young-Ah Seo, an assistant professor of nutritional biochemistry at the University of Michigan’s School of Public Health in Ann Arbor. The two-year grant was to end in August 2020 but will be extended 12 months because of a research pause during the COVID-19 pandemic.

Seo is investigating how a mutation in the WDR45 gene in BPAN individuals leads to iron accumulation and cellular damage. Her team was able to successfully generate a cell model of BPAN in which the WDR45 gene is deleted. This model showed significantly elevated iron levels, which suggests that the model mimics the condition seen in patients with BPAN.

Using this cell line, the team saw that the loss of WDR45 caused significant changes in the cellular pathways that regulate iron, which may underlie the reason iron accumulates in the brain of BPAN individuals. The team also found that the loss of WDR45 produces toxic reactive oxygen species, which are unstable molecules that can easily react and cause cell damage. This could contribute to the neurodegeneration seen in BPAN patients.

Taken together, the findings to date suggest that alterations in specific iron pathways increase total iron levels, promoting oxidative stress and cell damage in the BPAN cell model. Seo’s team is searching for molecular targets that can reduce iron levels in the cell model. Once the project is complete, it could point to potential therapies for BPAN.

 

October 2020

A research team in the Netherlands is making progress in its study of how mutations in the WDR45 gene affect beta-propeller protein-associated neurodegeneration (BPAN).

Dr. Mario Mauthe from the University of Groningen, Netherlands, received a $45,000 grant from the NBIA Disorders Association and this update is the results from that work.

The team is being led by Dr. Mario Mauthe of the University of Groningen, who in 2018 received a $45,000 grant from the NBIA Disorders Association and is updating us on the results from that work.

BPAN is one of the most common NBIA disorders, which share a common characteristic of iron accumulation in the brain. Researchers are trying to understand what causes the iron to collect in BPAN and its impact on disease symptoms.

The researchers first investigated whether a WDR45 mutation caused disruption in a cellular process known as autophagy, in which cells recycle damaged materials and get rid of waste. They wondered if that could explain the iron accumulation observed in the brains of BPAN patients.

The team observed that the absence of the WDR45 gene does not disrupt the natural process of autophagy but that cells carrying the mutation have defects in the mitochondria, which are the energy-producing compartments within a cell. Because other NBIA patients have mitochondrial defects, it could be common to multiple NBIA diseases.

Mauthe’s team is investigating whether or not the defective gene causes issues with autophagy specifically targeting mitochondria. More research is needed to sustain their hypothesis and to understand why this defect occurs and whether treating it would be a valuable avenue for future therapies.