title: Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.
abstract: The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP-protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, New York, USA.
authors.forename: Natura
authors.initials: N
authors.lastname: Myeku
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, New York, USA.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Clelland
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, New York, USA.
authors.forename: Sheina
authors.initials: S
authors.lastname: Emrani
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Kukushkin
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, New York, USA.
authors.forename: Wai Haung
authors.initials: WH
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alfred L
authors.identifier: http://orcid.org/0000-0002-8319-5856
authors.initials: AL
authors.lastname: Goldberg
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, New York, USA.|Division of Integrative Neuroscience in the Department of Psychiatry, New York State Psychiatric Institute, New York, New York, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duff
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D063347:Native Polyacrylamide Gel Electrophoresis; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D024801:Tauopathies / Q000378:metabolism*; D054875:Ubiquitination; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D016875:tau Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D020889:Rolipram