title: Na+/H+ exchangers induce autophagy in neurons and inhibit polyglutamine-induced aggregate formation.
abstract: In polyglutamine diseases, an abnormally elongated polyglutamine results in protein misfolding and accumulation of intracellular aggregates. Autophagy is a major cellular degradative pathway responsible for eliminating unnecessary proteins, including polyglutamine aggregates. Basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic function, but the regulatory mechanism for basal autophagy remains elusive. Here we show that the Na(+)/H(+) exchanger (NHE) family of ion transporters affect autophagy in a neuron-like cell line (Neuro-2a cells). We showed that expression of NHE1 and NHE5 is correlated to polyglutamine accumulation levels in a cellular model of Huntington's disease, a fatal neurodegenerative disorder characterized by accumulation of polyglutamine-containing aggregate formation in the brain. Furthermore, we showed that loss of NHE5 results in increased polyglutamine accumulation in an animal model of Huntington's disease. Our data suggest that cellular pH regulation by NHE1 and NHE5 plays a role in regulating basal autophagy and thereby promotes autophagy-mediated degradation of proteins including polyglutamine aggregates.
authors.affiliation: Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Togashi
authors.forename: Shuji
authors.initials: S
authors.lastname: Wakatsuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuno
authors.forename: Shinji
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D010455:Peptides; D017923:Sodium-Hydrogen Exchangers; C097188:polyglutamine