Archives     Advertise     Editorial Calendar      Advertiser Index     Subscribe     Contact Us    

Battling ALS

John Karijolich

VUMC Researchers Discover Role of Protein Linked to Neurodegenerative Diseases

Vanderbilt researchers are making headway in the fight against amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Vanderbilt researchers have discovered a protein implicated in conditions like ALS prevents the activation of an innate immune response that leads to cell death. The protein, called TDP-43, regulates the accumulation of double-stranded RNA -- genetic material found in both pathogens and in our own cells.

The findings, published in the journal Cell Reports, reveal an intricate relationship between innate immune responses and control of gene expression, said John Karijolich, PhD, associate professor of Pathology, Microbiology and Immunology. The discovery was led by graduate research assistant William Dunker and authors Xiang Ye, PhD; Yang Zhao, PhD; Lanxi Liu and Antiana Richardson.

Targeting ALS

William Dunker

"I was talking to John a year or two before this paper was published, throwing out new ideas, and started to look at how RNA binding proteins affect interferon responses," said Dunker, who received his bachelor of science in biochemistry from the University of Minnesota. "I was targeting several RNA binding proteins by knocking down and depleting them and focused on TDP-43 because of its role in ALS and other diseases."

Interferons are a group of signaling proteins made and released by host cells in response to the presence of viruses. TDP-43 is an essential RNA binding protein taking on several roles in the cell. Karijolich said cells can discriminate what should and shouldn't be present (i.e. an infection), and that double-stranded RNA is a sign there's something wrong in that cell.

According to a Vanderbilt release, TDP-43 is essential for cell viability (without it, cells die). The researchers found that reducing TDP-43 levels resulted in the accumulation of double-stranded RNA, activation of immune signaling pathways, and robust interferon production. Investigators pursued the idea that RNA binding proteins might act as controls to prevent the accumulation of "immunostimulatory" double-stranded RNA. They identified a collection of potential regulatory proteins and focused on TDP-43 because of its connection to neurological diseases such as ALS and frontotemporal lobar dementia (FTLD).

Digging Deeper

Karijolich said some patients with ALS and FTLD have elevated levels of interferon in their cerebrospinal fluid, supporting a link between TDP-43, immune pathway activation and neurological dysfunction. Dunker said there's evidence that inherently dangerous cellular RNAs are produced all the time, but through different mechanisms. "This paper looks at preventing immune responses and viewing gene expression as a double-edged sword with both good and bad aspects," he explained, noting significant findings surrounding double-stranded RNA in the past few years. Dunker's next step is to look at TDP-43's potentially broader role as a recruiter for various mechanisms of cell death, including possible therapeutic uses.

"We want to start targeting pathways to inactivate and prevent accumulation of interferons to prevent disease," said Karijolich, whose lab has studied double-stranded RNA receptors since 2016. "There might be cases where you want to activate it or turn the pathway off, so we're understanding what controls turning the pathway on or off. It's become obvious that the fundamental gene expression processes can activate the immune system, which is what led to Will's work digging into individual factors. It's helped bridge our thinking about cancer-causing issues and disease like ALS."

Karijolich continued, saying the discovery's significance to the greater healthcare community could mean more precise targeting of cells aimed at controlling the body's immune response. Dunker, who will graduate late 2021, also is leading a study on more effective treatment of herpes virus infections.

Other Neuroscience News of Note

Reducing Stroke Risk

In May, Vanderbilt researchers once again make headlines for their work on subarachnoid hemorrhage (SAH), or bleeding from a ruptured aneurysm. The condition leads to delayed cerebral vasospasm (blood vessel constriction) and stroke. SAH morbidity and mortality are high, and therapeutic options are limited.

Joyce Cheung-Flynn, PhD, and colleagues proposed that SAH downregulates the nitric oxide-protein kinase G (NO-PKG) signaling pathway that normally relaxes cerebral blood vessels. Using a rat model, they confirmed reduced levels of NO-PKG pathway molecules, including the protein VASP, which modulates contractile machinery to cause vasorelaxation. The team designed a family of cell permeant peptide mimics of activated VASP and demonstrated that the peptides caused vasorelaxation of vascular tissues ex vivo.

The findings, reported in the European Journal of Pharmacology, suggest that reduced NO-PKG signaling is an underlying mechanism of pathological vasoconstriction after SAH. Treatment with activated VASP peptides could be explored as a therapeutic strategy to reduce neurological deficits caused by SAH-induced vasospasm, the authors suggest.

Hope for Parkinson's Patients

Another VUMC paper released last year in Neurology represented the world's first study of deep brain stimulation, or DBS, for early stage Parkinson's, defined as within four years of disease onset. The study found a pair of ultra-thin electrodes surgically implanted deep into the brain might slow the progression of Parkinson's disease, according to five-year outcomes from a 30-patient randomized clinical trial conducted by investigators at Vanderbilt University Medical Center. David Charles, MD; Mallory Hacker, PhD; and colleagues are studying how deep brain stimulation might help slow tremor progression in early-stage Parkinson's disease patients.

Karijolich Lab


Related Articles:

Recent Articles

New Study Identifies Gaps in Treatment for Opioid Use Disorder as Overdose Emergencies Soar

Opioid overdose deaths have reached record highs and emergency physicians have a vital role in potentially saving these patients by prescribing Medication Assisted Treatment (MAT) such as buprenorphine, and by prescribing naloxone, a rapid-acting medicine to reverse an overdose.

Read More

HealthStream Acquires Rievent Technologies

Leveraging its hStream open architecture, HealthStream expands its ecosystem with a powerful continuing education management and delivery application

Read More


International Volunteer Day is a global celebration of volunteers. It takes place every year on December 5 to shine a light on the impact of volunteer efforts everywhere.

Read More

Tivity Health Takes Meaningful Steps to Keep Seniors Engaged, Connected

At first glance, SilverSneakers might appear to be 'just' a fitness class ... but dig a bit deeper, and it's clear this class is actually a community keeping participants active and engaged.

Read More

AMA Adopts Policy to Combat Public Health Disinformation by Health Care Professionals

New policy aims to address spread of rampant disinformation amid COVID-19 pandemic

Read More

AMA Adopts Policy Aimed at Strengthening U.S. Public Health Infrastructure, Opposing Limits Placed on Public Health Officials

New policy calls for consistent, sustainable funding, a robust public health workforce, and data modernization

Read More

Managing Risk of Cyber Incidents

Cyber threats are here to stay -- and they continue to be one of the topics keeping senior management up at night. With breaches and ransomware attacks still occurring at high rates, the healthcare industry continues to be significantly impacted.

Read More

American Cancer Society, Meharry Team Up to Change the Narrative

Meharry Medical College is one of four HBCUs partnering with the American Cancer Society.

Read More

Navigating Cancer Care

Nashville startup Thyme Care is proving to be an innovator in the cancer navigation space.

Read More

ONcology Rounds

New treatments, research and leadership - Middle Tennessee has a lot going on in oncology care.

Read More

Email Print



ALS, Antiana Richardson, John Karijolich, Lanxi Liu, Parkinson’s, SAH, Subarachnoid Hemorrhage, TDP-43, Vanderbilt University Medical Center, VUMC, William Dunker, Xiang Ye, Yang Zhao
Powered by Bondware
News Publishing Software

The browser you are using is outdated!

You may not be getting all you can out of your browsing experience
and may be open to security risks!

Consider upgrading to the latest version of your browser or choose on below: