title: Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species.
abstract: Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitin-negative, hyperphosphorylated tau species. CHIP-/- mice also have increased neuronal caspase-3 levels and activity, as well as caspase-cleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP-/- mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in post-developmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.
authors.affiliation: Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: Mei
authors.initials: M
authors.lastname: Yue
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Judith H
authors.initials: JH
authors.lastname: Dunmore
authors.forename: Wing C
authors.initials: WC
authors.lastname: Lee
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zehr
authors.forename: Gemma
authors.initials: G
authors.lastname: West
authors.forename: Songsong
authors.initials: S
authors.lastname: Cao
authors.forename: Amber M K
authors.initials: AM
authors.lastname: Clark
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Christopher
authors.initials: C
authors.lastname: Eckman
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D017353:Gene Deletion; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008970:Molecular Weight; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016875:tau Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C487100:chn-1 protein, C elegans; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases