TBK1 Protein Has Dual Role in ALS, First Accelerating It and Later Slowing It

Mutations in the TBK1 gene — often associated with amyotrophic lateral sclerosis (ALS) — seem to have a dual role in progression of the disease, causing it to emerge earlier in animals models of ALS, but then slowing in later stages.

This paradoxical role, according to a results of a study in mice, is likely due to the different cellular functions in which TBK1 participates, as it plays a key role in preventing the buildup of protein aggregates in motor neurons, but also is involved in the excess inflammation that causes progressive neurodegeneration in ALS.

The study, “The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice,” was published in the journal Neuron.

ALS is a neurodegenerative condition marked by the loss of motor neurons, the nerve cells that send electrical signals from the brain and spinal cord to the muscles, controlling their function.

The disease is triggered by the buildup of toxic protein aggregates in motor neurons, but cells that mediate immune responses in the brain (microglia) and provide support to neurons (astrocytes), also are central to its progression by causing inflammation and neurodegeneration.

“Neurodegenerative diseases such as ALS involve multiple cell types that are constantly changing as the disease progresses,” Tom Maniatis, PhD, the study’s lead author, explained in a press release. Maniatis is principal investigator at Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute.

As a result, signaling pathways involved in ALS also may change over time, “so a drug that is beneficial in the early stages of the disease could be detrimental at later times,” he said.

The TBK1 protein is involved in many cellular functions, including the autophagy process — which cells use to eliminate toxic or unneeded components — and in mounting an immune response against viruses and bacteria. While studies have implicated TBK1 in ALS, its exact function in disease onset and progression is not well understood.

“Because individuals with certain mutations in TBK1 have ALS, we wanted to develop a deep, mechanistic understanding of how these mutations affect cellular functions in the spinal cord during the course of the disease,” said Valeria Gerbino, PhD, an associate research scientist in the Maniatis lab.

Seeking to understand whether, and how, TBK1 participates in ALS, researchers at Columbia University partnered with The Jackson Laboratory and created different mouse models carrying TBK1 mutations that are associated with ALS in humans. All these mutations were deleterious, meaning they involved loss of function of the TBK1 gene and consequently little or no TBK1 protein production.

While TBK1 mutations caused no disease in otherwise healthy mice, they significantly changed disease course when inserted in an established model of ALS — SOD1 mice, which have a mutation in the SOD1 gene.

These mice developed motor symptoms earlier than SOD1 mice without TBK1 mutations (89 vs. 127 days), a reflection of an earlier damage to motor neurons and loss of communication between neurons and muscle cells. But, to scientists’ surprise, these mice lived 25% longer than SOD1 mice without TBK1 mutations.

The team then examined if those changes in disease progression were maintained if the TBK1 gene was deleted only in motor neurons of SOD1 mice, but not in other cells. In these mice, the disease also manifested earlier, but their lifespan was similar to SOD1 mice with a functioning TBK1 protein.

The reason for this, researchers found, was that TBK1 is involved in the autophagy process, helping motor neurons get rid of the toxic protein aggregates that cause ALS. If TBK1 did not function properly, these protein clumps would build up faster, causing damage to motor neurons in earlier stages.

However, TBK1 also is involved in the interferon-dependent immune response triggered by microglial cells and astrocytes. This immune response is needed to fight off invaders, but can be toxic to motor neurons when overactive. In the absence of TBK1, the interferon response was lowered, and motor damage was delayed.

“The loss of TBK1 in microglia and astrocytes clearly diminishes the interferon response in the spinal cord of ALS mice,” said Maniatis. “This correlates with significantly extending their lives.”

“In this study we showed that early in ALS disease progression the loss of TBK1 disrupts autophagy in motor neurons and accelerates ALS pathology,” the researchers explained. “However, as the severity of the disease advances with age, the loss of TBK1 function is beneficial due to a diminished immune response.”

“The identification of disease mechanisms on which multiple ALS genes converge, is the key for the discovery of potential therapeutic targets,” they concluded.