The most common pathologies seen in ASL is TDP-43, which occurs in greater than 90% of ALS cases. TDP-43 is encoded by the TARDBP gene, is a DNA/RNA binding protein that is implicated in RNA metabolism and is associated with mitochondria and mitochondrial defects. The pathology is defined as the aggregation of proteins that include phosphorylated form of TDP-43 protein. In this pathology, cells display nuclear membrane, ER and mitochondrial defects.

Mitochondria display ultrastructural defects in the upper motor neurons of ALS patients and mouse models of ALS. Upper motor neurons in the brain are responsible for initiating muscle movement and relaxation and are one of the first to break down in neurodegenerative diseases. Upper motor neuron degeneration is a defining characteristic of ALS. Therefore, understanding the cellular and molecular mechanisms responsible for their progressive degeneration is critical to finding effective therapies.

The researchers discovered a new phenomenon, which they termed mitoautophagy, that is a novel self-destructive path of mitochondrial degeneration. In this condition, mitochondria can clear themselves independently.

"I think we have found the culprit that primes neurons to become vulnerable to future degeneration: suicidal mitochondria," said senior study author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. "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."

"This type of degeneration begins much earlier than previously thought," said study lead author Mukesh Gautam, the A Long Swim (ALS) Ellen Blakeman fellow at Northwestern.

Using immune-coupled electron microscopy in 15 days old mice (equivalent to a toddler in humans), the researchers were able to investigate cellular processes within 200 neurons. They found that defective mitochondria were found in only certain cell types, primarily corticospinal motor neurons (CSMN). Moreover, the mitochondrial were in different stages of degeneration. The series of events that led to mitochondrial degeneration was thus coined mitoautophagy. It begins with elongation, stretching and folding of mitochondria, followed by unification of folded ends, and leading to disintegration of first the inner membrane followed by the outer membrane. The mitochondria were observed in a variety of stages, although primarily in stage III of degeneration.

These self-destructive mitochondria could be future targets for drug therapies to treat ALS and other neurodegenerative diseases. "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," Ozdinler said. "Maybe we don't need to reinvent the wheel to cure ALS and other neurodegenerative diseases. To overcome neurodegeneration, we need to improve the health and the stability of mitochondria. If we improve the health of the mitochondria early, we may even eliminate protein aggregate formation, a pathology broadly observed in many diseases."

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