Researcher dedicated to finding a cure for ALS

July 14, 2017
Mariana Pehar smiles in her lab
Dr. Mariana Pehar has worked at MUSC since 2012 studying Alzheimer's, Parkinson's, ALS and other neurodegenerative diseases. Photos by J Ryne Danielson

Few had heard of amyotrophic lateral sclerosis when Yankees first baseman Lou Gehrig caught his bad break in 1939.

“Today I consider myself the luckiest man on the face of the earth,” he told a sold–out Yankee Stadium in July of that year, two months after he benched himself due to the early symptoms of ALS. “I might have been given a bad break, but I’ve got an awful lot to live for.”

Less than two years after quitting baseball, he succumbed to the disease that would go on to bear his name.

ALS — or as it’s often called, Lou Gehrig’s disease — is a neurodegenerative disease affecting voluntary muscle control. As motor neurons in the brain die, muscles stiffen and eventually atrophy, resulting in difficulty walking, speaking, eating and breathing. The prognosis is almost invariably paralysis and death within a few years of the first symptoms. ALS has no cure, and its causes are a matter of conjecture among scientists. 

Mariana Pehar, Ph.D., is working to change that. Since coming to MUSC in 2012, she has dedicated herself to the study of neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS. Originally from Montevideo, Uruguay, she has been fascinated by the brain since she was young.

That fascination could someday lead to a cure for ALS. In studying the role of oxidative stress in the brain, she thinks she’s identified an interaction between certain signaling proteins that may be killing off motor neurons in ALS patients.

“We are trying to understand the mechanism by which motor neurons are dying,” Pehar said. “We have found that a protein called nerve growth factor (NGF), which regulates the growth and survival of neurons, is susceptible to post-translational modifications that can cause cell death rather than promote growth. In addition, we’ve identified two receptors, called RAGE and p75NTR, that interact to induce the cell death initiated by oxidized NGF."

Essentially, Pehar thinks NGF is being hijacked by chemically reactive molecules like free radicals and reactive sugar intermediates. These molecules are byproducts of normal metabolism, and the body has a defense system to cope with their production and prevent damage. In pathological conditions, however, this defense system is overwhelmed by the increased production of toxic molecules. Free radicals are linked to a host of diseases, including chronic inflammation, arthritis, diabetes and cancer. If Pehar is right, they may be behind neurodegenerative diseases like ALS and Alzheimer’s as well.

A $1.64 million grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, will help her test that hypothesis and could eventually lead to a cure for this rare but debilitating disease.

Pehar said identifying the interaction between RAGE and p75NTR is particularly important because they may be good therapeutic targets. “This is particularly interesting,” she said. “Cells communicate by secreting proteins such as NGF. But, for the process to work, the target cell must contain another protein called a receptor to recognize the incoming signal.”

Mariana Pehar uses a pipette while working in her lab
Dr. Pehar works in her lab to find the underlying causes of ALS.

Once a receptor recognizes a secreted protein, it triggers a signal cascade inside the target cell. Sometimes the signal causes the cell to grow or change in beneficial ways. Sometimes, it causes the cell to die.

That isn’t always a bad thing. The body needs a way to get rid of cells that are damaged beyond repair.

“An inflammatory response may be good at the beginning, if it’s well controlled,” Pehar explained. “Having a neuron that is not working properly — that’s not good. So, you want your body to get rid of it. But, when the process gets out of control, it can form a toxic feedback loop that becomes detrimental to healthy cells, too.”

For those working to cure ALS and other neurodegenerative diseases, the good thing about this complexity is that they might only have to target one piece of the process to short circuit the whole thing. None of these signaling proteins or receptors has the ability to induce a signaling cascade alone. It’s the interactions between them that trigger a response, good or bad, inside a cell.

“We’ve known about the potential involvement of p75NTR in ALS for many years,” Pehar said. “Other studies have experimented with eliminating p75NTR with minimal effect. The problem is that p75NTR interacts with many receptors and is important to the survival of neurons. Not having p75NTR is not good, and specifically preventing the death signaling without affecting its positive interactions is very complicated.”

As a result, the study of p75NTR’s involvement with ALS had fallen by the wayside. However, the discovery of RAGE and its interaction with p75NTR challenges the existing paradigm of ALS research and presents researchers with new therapeutic opportunities. 

Pehar and her team are taking a three-pronged approach.

“If we can prevent the interaction between p75NTR and RAGE, we think it might have a positive outcome,” she said. “We’re also trying to target the oxidized NGF and develop ways to remove p75NTR or RAGE from target cells using modified viruses called vectors.”

These viral vectors essentially act as tiny fighter jets, carrying precise genetic weapons to their targets while preventing collateral damage.

Pehar and her team are also developing a proof of principle study using animal models to observe how the absence of RAGE receptors might affect neurodegenerative processes. She hopes removing RAGE won’t have the same detrimental effects as removing p75NTR en masse.

“Over the next three to four years, we’ll continue trying to get a better understanding through animal models,” Pehar said. “After that, if we see a beneficial effect, its translation to the clinic may still lie many years ahead.” Nonetheless, Pehar said she is encouraged by these new discoveries and the advances that may be made over the next decade.