How suicidal power factories in brain cells trigger ALS

blue illustration of neurons
Northwestern University scientists have discovered a new phenomenon in which mitochondria in diseased upper motor neurons of the brain go through a self-destructive process, which could explain the early development of amyotrophic lateral sclerosis. (Colin Behrens)

Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of the motor neurons. But what triggers that decline of these critical cells?

Scientists at Northwestern University have discovered an unusual phenomenon in the brain that might explain the degeneration, opening up a potential new target for drug discovery.

In a study published in the journal Frontiers in Cellular Neuroscience, the researchers described how the power factories inside cells, known as mitochondria, go through a self-destructive process at an early stage of neurodegeneration. These neurons control muscle movement and relaxation, and they are among the first cells to malfunction in neurodegenerative diseases.

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The scientists named the phenomenon mitoautophagy. And in mouse studies, it was mostly observed in animals with the TDP-43 pathology—which makes up about 90% of ALS cases—but not in those with SOD1 mutations. TDP-43 is encoded by the TARDBP gene and regulates RNA metabolism.

Using a technique called immuno-coupled electron microscopy, the scientists analyzed more than 200 neurons from three different mouse models of ALS at 15 days old, which would be equivalent to a human toddler. Previous studies have shown that upper neurons in mouse and humans are similar at the cellular level, especially in TDP-43 cases.

They found that self-destructive mitochondria only affected diseased neurons. The cells' energy-producing structures first elongated, then formed ringlike structures and finally busted through their two membranes from the inside out, according to the researchers.

“I think we have found the culprit that primes neurons to become vulnerable to future degeneration: suicidal mitochondria,” the study’s senior author Hande Ozdinler said in a statement. “The mitochondria basically eat themselves up very early in the disease. This occurs selectively in the neurons that will soon degenerate in patient's brains.”

RELATED: Treating Parkinson's by restoring a waste-clearing mechanism

Since the mitochondria are crucial for ATP production and lipid stability, their health in the context of neurodegeneration has been a hot topic. A research team at Stanford University recently showed that failure of cells to remove an enzyme called Miro1 impedes their ability to remove damaged mitochondria, leading to the death of dopamine-producing nerve cells in Parkinson’s disease.

A collaboration between Capital Medical University in Beijing and the University of Iowa found that terazosin, a drug used to treat enlarged prostate, could activate an enzyme called PGK1 to help ease the energy shortage caused by malfunctioning mitochondria. After analyzing a large patient databank, the researchers found that Parkinson’s patients already taking PGK1 drugs showed better outcomes.

RELATED: Biogen's antisense ALS drug shows promise in early clinical trial

Most drug development efforts in ALS are focused on addressing the SOD1 alteration, the first genetic marker found in the inherited form of the disease. Biogen’s Ionis-partnered antisense drug tofersen, designed to reduce production of toxic misfolded SOD1 protein, recently showed promise in a phase 1 study. And Swiss biotech Neurimmune’s anti-SOD1 antibody also turned up positive preclinical results.

Ozdinler’s team believes self-destructive mitochondria could become a new target for developing drugs against ALS and other neurodegenerative diseases in which voluntary movement is affected. They are working with drug companies to see whether existing drugs for mitochondrial disease could be repurposed to heal motor neurons.

“Many of the drugs currently on the market that target the health and the integrity of mitochondria may well be repurposed and considered for neurodegenerative diseases in the future,” she said in a statement. “Maybe we don't need to reinvent the wheel to cure ALS and other neurodegenerative diseases.”

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