title: Co-expression of truncated and full-length tau induces severe neurotoxicity.
abstract: Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular-weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in the presence of full-length tau through the formation of nonfilamentous high-molecular-weight tau aggregates, in the absence of tau filaments. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies.
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Department of Neurology, University Hospital Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Ozcelik
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Department of Neurology, University Hospital Basel, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Sprenger
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Department of Neurology, University Hospital Basel, Basel, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: Skachokova
authors.affiliation: MRC, Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Fraser
authors.affiliation: Institute of Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Abramowski
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Clavaguera
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Probst
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Frank
authors.affiliation: Institute of Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: MRC, Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Tolnay
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Department of Neurology, University Hospital Basel, Basel, Switzerland.
authors.forename: D T
authors.initials: DT
authors.lastname: Winkler
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D000072416:Protein Structural Elements / Q000502:physiology; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins
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