TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities

Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal & bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.