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Neurotoxic impact of protein fragmentation and aggregation in tauopathy mouse models

Sprenger, Frederik. Neurotoxic impact of protein fragmentation and aggregation in tauopathy mouse models. 2017, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12193

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Abstract

The microtubule-associated protein tau and its pathological modification constitute the
central pathology of various human neurodegenerative diseases, including Alzheimer’s
disease (AD), collectively termed ‘tauopathies’. Abundant hyperphosphorylation and
aggregation of tau is a disease-defining hallmark, yet the underlying pathogenic and
pathophysiological processes have remained only partly understood. In addition, protein
fragmentation is a frequently observed phenomenon in the course of various
neurodegenerative diseases; however, the contribution of tau fragmentation to the
pathogenesis of tauopathies is still a matter of debate.
In our novel inducible mouse model, co-expression of truncated and full-length human tau
provokes axonal transport failure, mitochondrial mislocalization, disruption of the Golgi
apparatus and dysregulation of synaptic proteins associated with extensive nerve cell loss and
a severe neurological phenotype as early as 3 weeks of age. Of note, this was paralleled only
by the formation of soluble oligomeric tau species, and no insoluble filamentous tau
aggregates; therewith, identifying oligomeric tau species as toxic key players in tau pathology.
Despite continuous full-length tau expression, mice recovered from the neurotoxic insult once
truncated tau expression was halted. The induction of drastic but reversible neurotoxicity
highlights the neurotoxic potential of tau fragments as pathogenic mediators in
neurodegenerative disorders.
The present work implicates the complexity of protein fragmentation and oligomerization and
their neurotoxic impact in the context of tauopathies and aims for a better understanding of
the cellular mechanisms underlying tau toxicity.
Advisors:Winkler, David T. and Bettler, Bernhard
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
UniBasel Contributors:Bettler, Bernhard
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12193
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (142 Seiten)
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:52
Deposited On:27 Jun 2017 08:02

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