title: Brain Disorders Due to Lysosomal Dysfunction.
abstract: Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
authors.forename: Andrés D
authors.initials: AD
authors.lastname: Klein
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.|Dulbecco Telethon Institute, 80078 Pozzuoli, Italy.|Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, 80131 Naples, Italy; email: fraldi@tigem.it , settembre@tigem.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D001927:Brain Diseases / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*
keywords: TFEB; autophagy; lysosomal storage disorders; lysosome; neurodegenerative diseases; transcription factor EB; α-synuclein