Nirmala Nirinjini Naidoo, PhD
Research Professor of Medicine (Sleep Medicine), University of Pennsylvania
Biography
Nirmala Nirinjini Naidoo, PhD, is a Research Professor of Medicine (Sleep Medicine) and Chair of the Chronobiology and Sleep Institute Seminar Series at the University of Pennsylvania, Dr. Naidoo’s research focuses on proteostatic mechanisms underlying age related changes in sleep and wake regulation. She has established that sleep loss or sleep disturbances induce endoplasmic reticulum (ER) stress that up-regulates an adaptive homeostatic signaling pathway, the unfolded protein response (UPR). She has demonstrated that the UPR and proteostasis become impaired with aging. ER stress and the UPR are critical to the initiation and integration of pathways of inflammation as well as in the etiology of neurodegenerative diseases. Using two model systems, mouse and Drosophila, to carry out research on proteostasis mechanisms her group is unraveling the role of the UPR in behavior and pathologies. Her work has demonstrated that restoring proteostasis rescues the sleep phenotype in aged animals and cognition in aged and Alzheimer's disease mouse models. She has expanded her research to investigate the role of proteostasis mechanisms in Alzheimer's disease and in co-occurring conditions in Down Syndrome. Other research in her group is focused on the role of the synaptic scaffolding protein, Homer and its interaction with metabotropic glutamate receptors in the maintenance of wakefulness.
Q&A
Q: What motivated you to focus specifically on aging or neurodegeneration in your area of sleep research?
A: “Sleep-wake patterns changes dramatically as we age, becoming more fragmented both at night and during the day; there are frequent nocturnal awakenings, and increased daytime sleepiness Increasingly, research suggests that these changes are not just a normal part of aging but may actually contribute to neuronal stress and increase the risk for neurodegenerative diseases like Alzheimer’s. Our work aims to understand why sleep deteriorates with age and how disrupted sleep affects the aging brain. We have identified protein folding homeostasis, or proteostasis, as a key mechanistic link between sleep and brain aging. We have determined that sleep disruption impairs proteostasis, while proteostatic failure in turn exacerbates sleep fragmentation, establishing a bidirectional feed-forward loop that may promote neuronal dysfunction and neurodegeneration with age.”
Q: How does your work contribute to our broader understanding of the aging process or neurodegenerative diseases like Alzheimer’s or Parkinson’s?
A: “My work examines how protein quality control systems, particularly the unfolded protein response, become less effective with age and how that decline contributes to protein aggregation, cellular stress, and increased vulnerability of neurons. Loss of proteostasis is now understood as a core feature of aging and an important driver of neurodegenerative diseases like Alzheimer’s. Because sleep disruption directly interferes with proteostasis-related signaling, our research helps explain how poor sleep may contribute to neurodegeneration. Recent studies from our lab show that boosting protein-folding chaperones can restore cognitive function in both aged and Alzheimer’s disease mouse models, suggesting that proteostasis remains modifiable even later in life. Importantly, these interventions were beneficial even when started after significant pathology had already developed. We’ve also found that improving proteostasis leads to better sleep quality in aged mice, pointing to a bidirectional relationship between sleep and cellular stress. Ongoing work is testing whether these same approaches can improve sleep in Alzheimer’s disease models. Overall, our research highlights how restoring cellular stress resilience may slow or delay neurodegenerative disease progression.”
Q: Are there any innovative techniques or technologies that have significantly helped your work?
A: “In depth sleep analyses, calcium imaging in the brain as well as improved mouse models.”
Q: What has been the most challenging part of your research process so far?
A: “Staying funded.”
Q: What’s next for you in terms of future projects or research directions?
A: “I am currently working with a few Down syndrome mouse models examining sleep and early onset Alzheimer’s. Ultimately, we hope to move this work toward clinical studies.”
Recent Publications
- Mutant mouse models implicate a role for mGluR1/5, prolyl isomerase (Pin1) and Homer1a interactions in wakefulness
- Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice.
- Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome.
- Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer’s Disease mice