Kumar Sambamurti, PhD
Professor of Neurosciences
Neurodegeneration and Metabolism Laboratory
Our laboratory studies the molecular basis of neurodegeneration that leads to dementia or sensory failure. Alzheimer disease (AD) and a number of other neurodegenerative diseases are associated with accumulation of proteins such as the amyloid beta protein (Ab) a-synuclein and Tau in characteristic lesions that define these diseases. I have successfully graduated one Ph.D. student (Chitra Venugopal) and three Masters students (Christina Demos, Liu Fang, Robert Baranello) and co-mentored two Ph.D. students (Brice Williams and Javier Pacheco-Quinto) who have all secured excellent post-doctoral fellowships. I have also trained nine postdoctoral fellows who are all well situated in their careers. In addition, I am currently mentoring one graduate student and one post-doctoral fellow. Training in my laboratory is geared towards the development of detail-oriented scientists who can combine molecular biology, protein biochemistry, cell biology and anatomy to address key biomedical problems.
We are pursuing the hypothesis that failure of metabolic homeostasis leads to accumulation of several proteins and other metabolites to catastrophically overwhelm the cellular and systemic turnover pathways. Although, it is seductive to assume that toxicity of specific proteins causes neuronal dysfunction, several clinical trials that eliminated the Ab have failed to stop disease progression, demonstrating that the disease is far more complex than the toxicity of one or a. few proteins. The sum total of the damage caused by the failure of the clearance pathways is greater than that caused by the toxicity of individual proteins because the failure affects major pathways. Our laboratory has contributed to the understanding of the fundamental trafficking and turnover routes for critical membrane proteins. Another surprising finding in our lab showed that reduction of g-secretase may lead to a bypass of one or more Ab-degrading pathways to paradoxically yield higher levels of this protein. We also demonstrated that Ab is cleared via the lymphatic pathway from the brain. Another major direction is in the regulation of these pathways by major dietary metabolites, linking the pathologic accumulation with diabetes, hypercholesterolemia, and hyperhomocysteinemia. We have determined that metabolic modulation of amyloid attributed to cholesterol may actually reside in other metabolic intermediate-GGPP, instead. The laboratory is currently pursuing the idea that dietary macronutrients can influence the production of Ab and therefore serve as a useful therapeutic strategy for AD treatment. Specifically, we find that we can reduce Ab and improve behavior in mice by restricting one essential amino acid in mice.
Please check out our publications.