NBIA NEWS & INFORMATION

December 2020

- By Amber Denton

Amber and Sydney Denton of Houston, Texas

The fastest growing segment of our NBIA community, BPAN families, gathered virtually Nov. 17 for our first Zoom meeting hosted by NBIA Disorders Association.

With in-person gatherings restricted by the pandemic, we know that building strong relationships with families traveling the same journey is invaluable. Near or far, we are determined to support one another, and most of us have become quite familiar with Zoom.

Families of loved ones who have Beta-propeller Protein-Associated Neurodegeneration from the U.S. and Canada joined the call to catch up with friends, make new friends, ask questions and share stories during the two hour-long session. Families of young BPAN kids gained valuable insight from parents of BPAN adults. We laughed, we cried, we smiled, and we will do it again!

Our goal is to continue NBIA Zoom meetings to offer family support in 2021 and to expand to include meetings for PKAN, PLAN and MPAN in the first quarter of next year. Stay tuned for more information.

October 2020

A lab in Germany investigating the disease mechanisms in Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN) received a grant of €151,540 euros ($178,741 USD) from Hoffnungsbaum e.V, the German NBIA patient organization.

This 27-month study will be led by an experienced MPAN researcher, Dr. Arcangela Iuso from the Helmholtz Zentrum München in Munich.

Iuso’s goal is to reveal the cellular function of the C19orf12 gene and the protein it produces. MPAN is caused by a mutation in this gene and understanding how it functions is important to developing potential therapies. Specifically, Iuso and her team hope to understand the protein’s role in lipid metabolism, which is the breakdown of fats within the cell to store energy.

Iuso’s team hypothesizes that the normal functioning of the C19orf12 protein is disrupted, which could lead to an abnormal accumulation of cell products, such as lipids or iron. This can be the cause of the iron accumulation in the brain, a hallmark of NBIA disorders.

Hoffnungsbaum e. V., reports that the research team will include many cooperating scientists, such as Dr. Benjamin Engel at the Helmholtz Pioneer Campus. The organization went on to say that the laboratory will use a new technology called cryo-electron tomography to produce a three-dimensional image of the cells with fine molecular detail. By directly imaging proteins in action, cryo-electron tomography provides molecular insights into cellular processes and thus into disease mechanisms. The Iuso and Engel groups will image cells from MPAN patients, according to Hoffnungsbaum e.V.

Funding for the work was made possible from numerous fundraising campaigns and individual donations to Hoffnungsbaum e. V. Once researchers are able to understand the mechanisms of the disease, they can pave the way for developing treatments for MPAN and other NBIA disorders.

Collaborating partners for the MPAN research team investigating the role of C19orf12 in cell lipid metabolism are from left: PhD student Enrica Zanuttigh of Helmholtz Zentrum München, Dr. Lucia Berti of the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Dr. Benjamin Engel at the Helmholtz Pioneer Campus in Munich, project leader Dr. Arcangela Iuso, early-career scientist Dr. Tilak Kumar Gupta, and technical assistant Annett Hering from Helmholtz Zentrum Munich. Not pictured: Dr. Sophie Ayciriex from the Institute of Analytical Sciences at the University of Lyon, France.

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.