The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Recent work has continued to build on the importance of the ALP in the degradation of misfolded proteins that accumulate in many neurodegenerative diseases, and on elucidating further mechanisms of how disease features interact with the pathway. Enhancing the ALP in neurodegenerative diseases continues to be a focal point of therapeutic development. In particular, TFEB has emerged as a potent activator of the ALP by coordinating autophagy induction with lysosomal biogenesis, and its activation has successfully ameliorated disease in mouse models of various neurodegenerative disorders. Recent studies reveal that AD and PD exhibit a seeding and spreading phenomenon similar to that of prion disease. This phenomenon has driven the field to focus on the mechanics of seeding and spreading, and the role that autophagy may play. The autophagy–lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease. The autophagy–lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease. autophagy is a conserved degradation pathway. Three types of autophagy transport substrates to the lysosome where lysosomal enzymes degrade substrates. a class of genes encoding proteins facilitating the process of the ALP. the specific degradation of protein substrates with a pentapeptide KFERQ motif. the lysosomal gene network regulated by TFEB. TFEB binds to a consensus motif known as the CLEAR sequence in the promoter region to promote transcription of these genes. The CLEAR sequence consists of a palindromic 10 bp GTCACGTGAC motif, typically within 200 bp of the transcription start-site, and can be a single sequence or arranged in tandem with multiple copies. located on the lysosomal surface, this responds to lysosomal amino acid content by signaling to the nucleus, often via TFEB activation or inactivation. LYNUS consists of the mTORC1 complex, the V-ATPase complex, Rag GTPases, Ragulator, and Rheb. The V-ATPase complex senses amino acids and interacts with Rags and Ragulator. Rag GTPases physically bind to mTORC1 on the lysosomal surface and activate it. Activated mTORC1 phosphorylates TFEB to retain it in the cytoplasm. During starvation, mTORC1 is released from the LYNUS machinery and becomes inactive. mTORC1 can no longer phosphorylate TFEB, and unphosphorylated TFEB can then translocate to the nucleus to activate its target genes. the concept that lysosomal genes are regulated in such a way to provide optimal lysosomal function in various physiological and pathological conditions. TFEB is one such global regulator of the lysosomal gene network that responds to stress, starvation, and nutrient abundance, among other stimuli. functions within the cell to degrade old or damaged organelles, as well as long-lived or aggregated proteins too large to be handled by the proteasome. Basal autophagy functions in maintenance of the healthy cell. the direct engulfment of cytoplasmic cargo by the lysosome. a term used to describe an infectious protein particle. Prions can self-propagate and spread from one cell to another in a manner similar to a virus. a hypothetical model to describe prion replication. Seeds are oligomeric disease-associated forms of prion protein (PrPSc) that recruit monomeric cellular prion protein (PrPC) to form amyloid fibers. The amyloid fiber is fragmented to oligomers again to form more seeds and accelerate prion propagation. ensures proper organelle, macromolecule, and protein turnover in the cytosol. The process is also thought to arise in conditions of stress, specifically degrading protein aggregates and damaged mitochondria.