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.
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.