title: AMSH is required to degrade ubiquitinated proteins in the central nervous system.
abstract: Deubiquitination is a biochemical process that mediates the removal of ubiquitin moieties from ubiquitin-conjugated substrates. AMSH (associated molecule with the SH3 domain of STAM) is a deubiquitination enzyme that participates in the endosomal sorting of several cell-surface molecules. AMSH impairment results in missorted ubiquitinated cargoes in vitro and severe neurodegeneration in vivo, but it is not known how AMSH deficiency causes neuronal damage in the brain. Here, we demonstrate that AMSH(-/-) mice developed ubiquitinated protein accumulations as early as embryonic day 10 (E10), and that severe deposits were present in the brain at postnatal day 8 (P8) and P18. Interestingly, TDP-43 was found to accumulate and colocalize with glial marker-positive cells in the brain. Glutamate receptor and p62 accumulations were also found; these molecules colocalized with ubiquitinated aggregates in the brain. These data suggest that AMSH plays an important role in degrading ubiquitinated proteins and glutamate receptors in vivo. AMSH(-/-) mice provide an animal model for neurodegenerative diseases, which are commonly characterized by the generation of proteinaceous aggregates.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Suzuki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Masanao
authors.initials: M
authors.lastname: Kyuuma
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases; D051379:Mice; D008817:Mice, Mutant Strains; D019636:Neurodegenerative Diseases / Q000201:enzymology*; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D010450:Endopeptidases; D045726:Metalloproteases; C441451:Stambp protein, mouse; D043222:Ubiquitin Thiolesterase