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.

Karijolich Lab