Buck Institute for Research on Aging

Role of Pharmacologically Induced-TFEB in Aging and Age-Related Neurodegeneration

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A characteristic feature of aging and many age-related diseases is enhanced accumulation of damaged cellular organelles and proteins. There is growing evidence, which suggests that defective autophagy is a major underlying factor resulting in these features. Autophagy helps in clearance and recycling of damaged,non-functional proteins and cellular organelles within lysosomes. Studies in mammals have uncovered that the helix-loop-helix transcription factor EB (TFEB) is a central regulator of autophagy. Consequently, TFEB is shown to be critical for multiple cellular processes including mitochondrial function, lipid metabolism and immune responses. Recent literature, including the work from our lab has shown that reduced TFEB expression underlies many neurodegenerative diseases. Conversely, enhancing TFEB expression rescues pathologies associated with these diseases,making it an important therapeutic target. With this rationale in mind we screened natural product library (NPL640)and their derivatives for their efficacy fort ranscriptionally inducing TFEB. From the neuronal cell culture based screen, we identified a series of potent TFEB-inducers. As part of my funded Larry Hillblom fellowship, I proposed to study the role of TFEB inducers in greater detail and, in the process, understand how a decline in TFEB-mediated autophagy leads to aging and age-related neurodegeneration.