Modifying factor: Researchers identify modifier of key protein in rare neurological diseases

By Sarah Kiefer | Bond LSC

It takes a keen detective to sleuth out why and how particular genetic mutations present the severe symptoms seen in neurological diseases.

The labs of Chris and Monique Lorson are one step closer to understanding one piece in the puzzle for spinal muscular atrophy with respiratory distress (SMARD1) and Charcot Marie Tooth 2S (CMT). They recently identified that the protein ABT1 appears to regulate the activity of IGHMBP2 by means of its interaction with it.

Their NIH-supported studies were recently published in JCI Insight with lab member Gangadhar Vadla as first author.

IGHMBP2 is a protein that causes SMARD and CMT2S. In these two rare neurodegenerative diseases, people inherit a mutated IGHMBP2 gene from each parent. The primary clinical presentation for SMARD1 is respiratory distress and without intervention patients typically die within the first two years of life. CMT2S, while less severe than SMARD1, presents with motor function and coordination defects that substantially impact patients’ lives. SMARD1 and CMT2S patients both demonstrate degeneration of the motor neurons within the brain and spinal cord.

The Lorson’s have built a career out of investigative work, looking into spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress (SMARD1), and Charcot Marie Tooth types 1A, 2S and 2E.

When it comes to SMARD1 and CMT2S, understanding how cellular processes are altered when IGHMBP2 is mutated, and how particular mutations present in a clinical setting, is key towards developing therapeutic options.

The Lorson labs approach these studies using genetics and biochemistry. They  generated a series of mice with Ighmbp2 mutations that correlate with patient mutations, showing traits of SMARD1 or CMT2S, depending on what particular Ighmbp2 mutation is present.

“ABT1 is the first protein found to modify the SMARD1 phenotype in mice through its association with IGHMBP2”,  said Vadla, a postdoctoral fellow in the Lorson Lab.

They identified ABT1 as a modifier using an ABT1 gene therapy approach.

“Animals receiving the ABT1 gene therapy showed modest improvements in lifespan and motor function tests, consistent with a modifier, while untreated animals did not, “ Monique Lorson said.

The Lorson lab addressed three primary questions: do IGHMBP2 and ABT1 associate and how stable is this interaction, second, does this interaction change any of the activities associated with IGHMBP2 and, if so, what activities, and, third, can we use this interaction to understand what the role of the IGHMBP2-ABT1 complex is within cells.

“These questions, while seemingly simple, are really important in that is unknown how mutations in IGHMBP2 lead to SMARD1 or CMT2S, “ said Monique Lorson.

Their results demonstrate a strong association between IGHMBP2 with ABT1, and that  binding of IGHMBP2 with ABT1 significantly increases biochemical activity of the IGHMBP2 protein. The studies also provided evidence towards the potential role of this complex in 47S pre-rRNA processing. 47S pre-rRNA processing is necessary to generate ribosomes used in the process of translation. Translation is the process cells use to make proteins.

“Because translation is required to make proteins, if you don’t have proper 47S pre-rRNA processing, some aspects of translation will be significantly impacted, putting the cell under a lot of stress,” said Monique Lorson. “The big goal now is demonstrating that 47S pre-rRNA processing and translational defects are present in Ighmbp2 mutant mice and that these defects result in disease.”

Now, the Lorson lab is testing their findings by creating IGHMBP2 that mirror those seen in real patients to study whether the interaction between IGHMBP2 and ABT1 is altered in any of these mutants.

Why is this finding important?

ABT1 is the first protein found that modifies the severity of disease in Ighmbp2 mutant mice. This is one step towards understanding how IGHMBP2 protein functions within cells and how mutations in IGHMBP2 lead to disease. The progress is only possible with involvement from many Lorson lab members and Bond LSC collaborator Kamal Singh.

“Everyone came together and played an important role, “ Monique Lorson said.  “The Lorson lab works well as a team because we all try to make each other better scientists.”

This project was special to the Lorson family as it was the first time Chris, Monique and their son, Zachary Lorson, published their findings together.

She finds this work maintains her passion for science because she hopes their contributions can someday make a positive impact on SMARD1 and CMT2S families.

“When you feel like you can make a difference and not only impact people’s quantity of health, but also quality of health,” Monique Lorson said. “That makes coming into work really easy.”

Gangadhar P. Vadla, Sara M. Ricardez Hernandez, Jiude Mao, Mona O. Garro- Kacher, Zachary C. Lorson, Ronin P. Rice, Sarah A. Hansen, Christian L. Lorson, Kamal Singh and Monique A. Lorson authored “ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity.” It appeared in the journal JCI Insight in December 2022.

Article originally published on Decoding Science.