Summary: A previously overlooked cellular structure known as the Nageotte nodule, described over a century ago, has been found to play a crucial role in diabetic neuropathy according to new research. These nodules, formed from decayed sensory neurons and supporting cells, were discovered in large quantities within the sensory ganglia of diabetic organ donors.
The study indicates that these nodules not only reflect nerve degeneration but might also contribute to pain by generating abnormal, pain-sensitive axons. This insight could transform the approach to treating diabetic nerve pain, highlighting the importance of early neuroprotection before these nodules develop.
Key Facts:
- Forgotten Clue: Nageotte nodules, long ignored, are prevalent in diabetic neuropathy.
- Pain Pathway: These nodules harbor axons likely responsible for pain generation.
- New Focus: The findings propose that addressing early neurodegeneration could avert nerve damage.
A little-understood phenomenon that has been largely overlooked since its discovery a century ago is now recognized as a vital element of diabetic pain, as highlighted by research from The University of Texas at Dallas’ Center for Advanced Pain Studies.
Research published in Nature Communications on May 5 reveals that clusters of cells known as Nageotte nodules serve as significant indicators of nerve cell death in human sensory ganglia.
This could pave the way for developing medications aimed at protecting nerves or managing diabetic neuropathy.
“The key takeaway from our study is that it reshapes our understanding of diabetic neuropathic pain,” stated Dr. Ted Price, Ashbel Smith Professor of neuroscience at the School of Behavioral and Brain Sciences, CAPS director, and co-corresponding author of the research.
“Our findings suggest that neurodegeneration in the dorsal root ganglion is a critical aspect of the condition that should prompt a reevaluation of the disease’s approach.”
Diabetic neuropathy is among the most common types of neuropathic pain, affecting around 11 million individuals — nearly a third of the 38 million diabetics in the United States, as indicated by the CDC. It primarily targets the extremities, causing sharp, shooting discomfort.
“Diabetic neuropathy can be quite debilitating,” emphasized neuroscience research scientist Stephanie Shiers, a co-corresponding author.
“Treatment options are limited, and without proper management of the underlying diabetes, individuals might face amputations due to severe nerve damage leading to loss of sensation.”
Supported by a National Institutes of Health Research Program Cooperative Agreement grant, Shiers and her colleagues at CAPS are working on mapping human dorsal root ganglia and other sensory system tissues to enhance the understanding of human pain mechanisms.
“I observed a significant presence of these Nageotte nodules in specific dorsal root ganglia from organ donors. Upon reviewing their medical histories, all were diabetic,” she explained.
“These nodules were notably more common in diabetic individuals, especially those with diabetic neuropathy. It was a major finding to see these abnormalities across such a large portion of tissue with consistent medical backgrounds.”
Nageotte nodules consist of ruined sensory neurons, leaving behind clusters of non-neuronal cells. Initially documented in 1922 by French neuroanatomist Jean Nageotte, these nodules have been mainly ignored in research over the past century, appearing in only about 20 studies, many decades old.
“They appear to signify degeneration resulting from hyperglycemia impairing neuron survival,” Shiers remarked.
“Very little has been recorded regarding the molecular composition of these structures. Virtually no one in the pain research community was familiar with them, and we knew close to nothing about their role in pain and neurodegeneration.”
This study aimed to explore Nageotte nodules at the molecular level.
Through histology and spatial sequencing, they showed that Nageotte nodules are prevalent in sensory ganglia of patients with diabetic neuropathy, primarily comprising satellite glia and non-myelinating Schwann cells.
“Intermixed within the nodule is a collection of axons: sensory neuron fibers resembling small neuromas. The axons seem to sprout from sensory neurons; they are pain-sensitive fibers,” Shiers noted.
“This appears to be a unique pathological finding — something never previously described in humans.”
If proven, this discovery could lead to new treatment strategies.
“The spontaneous activity in these fibers may be a fundamental cause of diabetic neuropathy,” Shiers added. “We also identified several donors with various neuropathic conditions that were not diabetes-related, and their DRGs also exhibited numerous Nageotte nodules.”
Unlike earlier literature that primarily discusses individual case studies of Nageotte nodules, this research includes samples from 90 individuals. Shiers emphasized that her documentation of axon sprouting signifies a new discovery — yet another dimension this study unveils.
“This research might alter our fundamental understanding of sensory neurons. Typically, sensory neurons do not sprout fibers from their cell bodies; they have a distinct pseudounipolar shape, but these diabetic sensory neurons appear multipolar.” Shiers stated.
“We are still unsure whether this morphology is problematic or if it reveals a lack of understanding of these cells in humans.”
The capacity to study human dorsal root ganglia from such a diverse range of patients is attributed to the work of the Southwest Transplant Alliance, a nonprofit organization that recovers donated organs and tissues for transplantation.
“The ability to contribute to research that offers hope to those facing loss is incredibly significant for our donation community,” stated Brad Adams, President and CEO of the Southwest Transplant Alliance. “Knowing that your loved one’s donation led to remarkable medical breakthroughs brings solace and healing to those who have experienced loss.”
Price remarked, “This study wouldn’t have been possible without their contributions. This partnership is essential for enabling this work.”
Price noted that the research has sparked new approaches to understanding neuropathy.
“In my perspective, one of the most crucial insights from this work is the necessity to rethink our treatment methods for diabetic neuropathic pain. We should perhaps prioritize neuroprotection in the early stages of the disease, aiming to prevent the formation of these Nageotte nodules.”
Other affiliated authors from UT Dallas include Dr. Gregory Dussor, Dr. Diana Tavares Ferreira, Andi Wangzhou, Dr. Joseph Lesnak, Ishwarya Sankaranarayanan, Khadijah Mazhar, and Nwasinachi Ezeji. Additional contributors hail from the Southwest Transplant Alliance and The University of Adelaide in Australia.
Funding: This research received support from the National Institute of Neurological Disorders and Stroke through grants U19NS130608 and R01NS111929.
