Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer's disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately over- express TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. In this project, we will determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and determine if soluble factors secreted by muscle (?myokines?) mediate the beneficial CNS effects in conditional skeletal muscle- expressing TFEB transgenic mice. Identification of pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS.
The importance of proteostasis to health and disease is well documented, yet how this process is regulated in a whole organism context remains poorly understood, especially in mammals. Individual organs in the body, particularly skeletal muscle, may play a pivotal role in regulating proteostasis in other tissues; hence, this project investigates the role of skeletal muscle-expressed Transcription factor E-B (TFEB), a master transcription factor regulator of autophagy and cellular clearance, in promoting CNS proteostasis during aging. These studies will address muscle-to-brain cell-non autonomous proteostasis signaling, determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and establish if soluble factors secreted by muscle (?myokines?) mediate beneficial CNS effects in conditional skeletal muscle-expressing TFEB transgenic mice, in the hope that such work may yield therapeutic opportunities for promoting CNS quality control pathways and function in age-related brain diseases.
|Cortes, Constanza J; La Spada, Albert R (2018) TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities. Neurobiol Dis :|