Numbing intraneuronal Tau levels to prevent neurodegeneration in tauopathies
Montreal Clinical Research Institute (IRCM)
Abstract
Intraneuronal accumulation of the microtubule associated protein Tau is largely recognized as an important toxic factor linked to neuronal cell death in Alzheimer’s disease and tauopathies. While there has been progress uncovering mechanisms leading to the formation of toxic Tau tangles, less is known about how intraneuronal Tau levels are regulated in health and disease. Here, I will discuss our recent work showing that the intracellular trafficking adaptor protein Numb is critical to control intraneuronal Tau levels. Inactivation of Numb in retinal ganglion cells increases monomeric and oligomeric Tau levels and leads to axonal blebbing in optic nerves, followed by significant neuronal cell loss in old mice. Interestingly, overexpression of the long isoform of Numb (Numb-72) decreases intracellular Tau levels by promoting exocytosis of monomeric Tau. In TauP301S and triple transgenic AD mouse models, expression of Numb-72 in RGCs reduces the number of axonal blebs and prevents neurodegeneration. Finally, inactivation of Numb in TauP301S mice accelerates neurodegeneration in both the retina and spinal cord and leads to precocious paralysis. Taken together, these results uncover Numb as a essential regulator of Tau homeostasis in neurons and as a potential therapeutic agent for AD and tauopathies.
Topics
Related Seminars
Finding Meaning in Memories
Daphna Shohamy and Ashok Litwin-Kumar bridge experimental and computational neuroscience to explain how the brain assigns significance to memories, how dopamine shapes memory-guided decisions, and…
Deciphering the Dynamics of the Unconscious Brain under General Anesthesia
Stanford Neurosciences Seminar Series talk by Emery Brown (Massachusetts Institute of Technology, Neuroscience Statistics Research Lab) on deciphering the dynamics of the unconscious brain under…
The Connectome in Use: From anatomical wiring to functional organization in the behaving C. elegans brain
Rani Borbara presents brain-wide recordings from more than 150 freely moving C. elegans to examine how anatomical connectivity becomes functional organization during behavior. Cross-animal models…
Related Job Opportunities
Research Associate (Fixed Term)
We seek a highly motivated Postdoctoral Research Associate to join the laboratory of Professor Kathy Niakan. We are based in the Loke Centre for Trophoblast Research (LCTR), in the Department of…
Postdoctoral Scientist - Sarvestani Lab
The Sarvestani Lab at Cornell University is recruiting a postdoctoral scientist in systems neuroscience to study how visual and motor systems across the brain and body support perception and…
PhD Studentship: Mitochondrial Metabolism and Novel Therapeutic Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (Fixed Term)
Supervisors: Professor Andrew Murray, Department of Physiology, Development and Neuroscience, University of Cambridge Dr Ross Lindsay, Novo Nordisk Funding: Fully funded PhD studentship (Home/UK…