Northwestern Medicine scientists have zeroed in on a cellular gatekeeper that may hold promise for treating abnormal protein accumulation in neurodegenerative diseases, according to a study published in Nature Communications.
“In all neurodegenerative diseases, there is an accumulation of misfolded proteins,” said Robert Kalb, MD, the Joan and Paul Rubschlager Professor, chief of Neuromuscular Disease in the Ken and Ruth Davee Department of Neurology, and director of the Les Turner ALS Center, who was senior author of the study. “We think that these misfolded proteins are a target for disease — the disease is actually driven by the accumulation of these misfolded proteins.”
In the current study, Kalb and his collaborators aimed to investigate the role of RAD23, a protein that is involved in the identification and disposal of damaged or misfolded proteins. Under normal circumstances, elimination of misfolded proteins is essential for maintaining a healthy collection of proteins in cells, a process known as protein homeostasis, or proteostasis.
Proteostasis is essential for physiological cell function, operating to balance the creation and destruction of proteins. When this balance breaks down, misfolded proteins can accumulate and form toxic aggregates, a hallmark of diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s, Huntington’s and Alzheimer’s disease.
First, Kalb and his team performed a genetic screen in C. elegans models of ALS and found that the protein RAD23 plays a dual role: it helps degrade some proteins while stabilizing others.
His team showed that loss of RAD23 from cells accelerates the breakdown of several disease-linked proteins — including mutated forms of TDP43 and SOD — suggesting that physiological levels of RAD23 may actually hinder the cell’s ability to clear harmful protein aggregates.
Next, scientists targeted two mammalian versions of the protein — RAD23A and RAD23B — using genetic tools and anti-sense oligonucleotides (ASOs) in a mouse model of ALS. They observed that reducing the abundance of RAD23A enabled the disease mice live longer, retain strength and this intervention also blunted the accumulation of misfolded proteins, according to the findings.
“When we administered ASOs to this mouse model of disease, we found this really robust effect on survival, behavior and rescued cell death,” Kalb said. “I’m interested in the RAD23A biology, but I also see a potential pathway for therapeutics here using RAD23A-targeting ASOs.”
By binding to misfolded proteins and the proteasome (the cell’s protein disposal unit), RAD23 may physically or chemically block the proteasome’s function. This interference could impair the cell’s ability to maintain proteostasis, contributing to disease progression, Kalb said.
The findings have the potential to pave the way for novel therapeutic strategies that enhance the body’s natural ability to clear toxic proteins, Kalb said.
“In neurodegenerative diseases, essentially every rock that you look under, you’ll find an abnormality,” Kalb said. “Because TDP43 is so prevalent in neurodegenerative diseases, this approach has the potential to have a broad beneficial effect.”
Moving forward, Kalb and his collaborators will continue to study the mechanisms behind misfolded protein aggregation and how cutting-edge technology could aid in treating diseases such as ALS.
“When it comes to the science of understanding and treating neurodegenerative disease, it can be a tricky business,” Kalb said. “We have to be willing to serve up a lot of ideas and investigate every option. The scientists in my lab and I are committed to this mission of understanding these diseases from every angle.”
The study was funded by the National Institute of Neurological Disorders and Stroke, the U.S. Public Health Service (NS122908 and NS124802), the U.S. Department of Defense (W81XWH-21-1-0236), the Les Turner ALS Foundation and the Heather Koster Family Charitable Fund.
