New study links type 1 narcolepsy to damage in second brain region
Findings may help explain sleepiness and sudden muscle weakness
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Type 1 narcolepsy has long been linked to the loss of nerve cells called hypocretin neurons in a brain region called the hypothalamus, but a new study suggests damage to a second brain region, called the locus coeruleus, is also involved.
This finding may help explain why people with this form of narcolepsy experience bouts of sudden muscle weakness in addition to sleep-related symptoms, and may have important implications for how the disease is diagnosed and treated.
“This doesn’t overturn what we know about hypocretin and narcolepsy, but it does suggest we’ve been looking at only part of the picture,” Jerome Siegel, PhD, the study’s senior author at the University of California, Los Angeles (UCLA), said in a university news story. “Understanding the full scope of the neurological changes in narcolepsy patients is essential if we want to develop more targeted therapies.”
Study may broaden understanding of narcolepsy
An early version of the study, “Human narcolepsy is linked to degeneration of both locus coeruleus and hypocretin neurons,” was published in Nature Communications. The work was funded by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs.
The study focused on narcolepsy with cataplexy, also known as type 1 narcolepsy, which is marked by excessive daytime sleepiness and cataplexy, or sudden loss of muscle tone. More than two decades ago, Siegel’s team helped establish that this form of narcolepsy is marked by loss of hypocretin neurons in the hypothalamus.
Because the hypothalamus is a brain region key for regulating sleep, loss of hypocretin neurons in this region has long been thought to be a main driver of sleep problems in the disease. But hypocretin neuron loss alone has not fully explained why people with type 1 narcolepsy experience cataplexy.
The new results may help explain this longstanding scientific mystery. By analyzing postmortem brain tissue from 11 people with narcolepsy type 1 and five people with no neurological disease, the team found that, as expected, all patients showed loss of hypocretin neurons in the hypothalamus. But strikingly, the hypothalamus wasn’t the only affected brain region.
Data showed that every narcolepsy patient also showed loss of neurons in the locus coeruleus, a brain region involved not only in regulating sleep, but also in controlling muscle tone.
In each sample, the total number of neurons in this region was abnormally low, but the remaining cells were abnormally large. The researchers said this suggests the remaining cells may be working harder to compensate for the loss.
“The locus coeruleus has both upward connections that contribute to wakefulness and downward connections that help maintain muscle tone,” said Thomas Thannickal, PhD, the study’s first author at UCLA. “That makes it a compelling candidate for explaining both of the defining symptoms of narcolepsy of sleepiness and cataplexy in a way that the neuronal degeneration in the hypothalamus alone does not fully account for.”
Immune response may affect both brain regions
One potential explanation for these findings might be that loss of hypocretin neurons in the hypothalamus leads to damage in the locus coeruleus as a consequence. But experiments in mouse and dog models of narcolepsy suggested this is not the case: even in models with hypocretin loss or hypocretin receptor changes, the locus coeruleus was intact, suggesting that damage in this region isn’t just a byproduct of hypocretin neuron loss.
Instead, the researchers said the findings support the idea that immune-related mechanisms may affect both brain regions. Supporting this idea was the discovery that people with narcolepsy type 1 had higher numbers of microglia, the brain’s resident immune cells, in these regions than people without neurological disease.
“Our findings support the idea that the autoimmune mechanisms driving human narcolepsy extend to both … hypocretin neurons and [nerve cells in the] locus coeruleus,” the team wrote.
The researchers also found deposits of tau and alpha-synuclein — proteins associated with Alzheimer’s and Parkinson’s disease — in the locus coeruleus of people with narcolepsy type 1. The authors said the implications of this finding need further study. More broadly, the scientists are hopeful that further studies into the role of the locus coeruleus in narcolepsy may lead to improved care for patients.
“Currently, narcolepsy is often diagnosed long after the initial neural damage has occurred,” Thannickal said. “By identifying specific biomarkers linked to the health of the locus coeruleus, clinicians could achieve earlier detection by non-invasive techniques before significant neuronal loss.”
“Integrating locus coeruleus degeneration with hypocretin neuron loss fundamentally broadens our understanding of narcolepsy’s neuropathology. With advances in neuroimaging, molecular biology, and immunotherapy, the findings offer a roadmap for future translational endeavors,” Thannickal added.
