Searching for the cause of ALS, researchers look to metabolism within cells

One distinct hallmark of ALS is the dysfunction of a tiny protein called TDP-43.

This protein normally lives within a cell’s nucleus, but in the case of ALS, it becomes dysfunctional, migrates out, and aggregates into the cell’s cytoplasm.

The vast majority of ALS cases show this protein aggregation, and it’s believed that this dysfunction that leads to neurodegeneration of brain cells.

But why does TDP-43 become dysfunctional in the first place? That’s the million-dollar question that scientists worldwide are trying to answer.

At the Les Turner ALS Center at Northwestern Medicine, a trio of researchers formed a unique hypothesis: What if the mitochondria—the powerhouses of a cell—were the triggers of this defect?

After all, mitochondria play a central role in a cell’s metabolism by generating energy to power biochemical reactions, and studies have shown metabolic defects often precede ALS onset.

Leading the charge to find out are Evangelos Kiskinis, associate professor of neurology and neuroscience, and Navdeep Chandel, the David W. Cugell, MD, Professor of Medicine and of Biochemistry and Molecular Genetics and an expert in mitochondria. Both are part of Northwestern University’s Feinberg School of Medicine.

With a grant from the Les Turner ALS Foundation, the pair and MD/PhD student Evan Kaspi have spent years trying to find out.

Working with Kiskinis’s induced pluripotent stem cell (iPSC) platform—which allow researchers to grow motor neurons derived from blood samples of people living with ALS patients—they studied motor neurons in human plasma-like medium, which mimics conditions inside the human body.

They studied the metabolism inside motor neuron cells to see if it causes this protein dysfunction. But interestingly, their hypothesis hasn’t panned out so far.

“At this stage, we don’t believe that metabolic dysfunction triggers TDP-43 dysfunction, but our efforts are ongoing,” Kiskinis said.

Still, as scientists, they look at negative data as more interesting than positive data. The team would still like to test their hypothesis in a mouse model, and they are exploring alternative ways by which mitochondrial alterations could be implicated in ALS.

“It’s not as simple as we had hoped, but that doesn’t mean it’s not there,” Chandel said. “We don’t want to go in with a bias and see what we want to see, and we’re going to be careful to test other aspects of metabolism.”

“Abnormalities in fuel utilization by neurons is common in neurodegenerative diseases, and there is much evidence that it contributes to ALS,” said Robert Kalb, director of the Les Turner ALS Center at Northwestern Medicine. “We do not know if metabolic dysfunction is a consequence of other abnormalities in ALS cells or is a driver of pathology. It may turn out that both ideas are in play at different times during disease progression. The work by this team is an important contributor to our understanding of metabolic abnormalities in ALS and will lead to further explorations in this complex and interesting research space.”

Grants from the Les Turner ALS Foundation fund seed research like this, allowing researchers to test hypotheses that might ultimately change course based on data.

“We’re incredibly grateful to the steadfast support of the foundation, particularly during a challenging time for research,” Kiskinis said. “It allows us to explore more adventurous ideas and generate data that allow us to pursue larger grants. My lab would not have been able to maintain a sustained effort and focus on ALS without the foundation.”