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

AACR Establishes New Cancer Evolution Working Group

The American Association for Cancer Research (AACR) announced the formation of its seventh and newest scientific working group, which will be dedicated to supporting cancer evolution research.

Read More

Global Dementia Cases Forecasted To Triple By 2050

New analysis shows a decrease in prevalence due to education countered by increase due to heart health risk factors

Read More

Blackburn, Feinstein Introduce Bill to Protect Access to Breast Cancer Screenings

U.S. Senators Marsha Blackburn (R-Tenn.) and Dianne Feinstein (D-Calif.) today introduced the Protecting Access to Lifesaving Screenings (PALS) Act of 2021, a bill to preserve coverage for routine breast cancer screening for women beginning at age 40.

Read More


The company's 2020 sustainability report highlights its commitment to environmental, social and governance (ESG) activities

Read More

Mobile Mentor Named Winner of Microsoft's 2021 Partner of the Year for Modern Endpoint Management

Mobile Mentor announced they have been awarded the 2021 Global Partner of the Year Award for Modern Endpoint Management.

Read More

Alzheimer's Association Welcomes CMS Announcement of National Coverage Determination Analysis on Treatment for Alzheimer's Disease

On behalf of all those living with Alzheimer's disease, their caregivers, and their families, we appreciate the Centers for Medicare & Medicaid Services (CMS) thoughtful consideration on coverage considerations for monoclonal antibodies targeting amyloid for the treatment of Alzheimer's disease, including aducanumab, which was recently approved by the Food and Drug Administration (FDA).

Read More

HCTec Acquires Talon Healthy IT Services

Healthcare IT firm adds industry-leading help desk service company to portfolio of solutions

Read More

The Seven Steps of Revenue Cycle for a Healthcare Practice

Revenue cycle management tracks patient revenue from the initial encounter with the healthcare system to payment of balance. Getting the seven steps of revenue cycle right helps providers avoid missteps that are costly to the bottom line.

Read More

Expanding Evidence-Based Care for Dementia

The Alzheimer's Association is on a mission to ensure care professionals have access to evidence-based training to ensure those with dementia receive quality care across all settings.

Read More

A Natural Leader

Nashville physician Dr. Ryan Mire to head nation's largest medical-specialty society.

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: