title: Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation.
abstract: Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Emma
authors: E
authors: Mead
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Dimitra
authors: D
authors: Kestoras
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Yolanda
authors: Y
authors: Gibson
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Lucy
authors: L
authors: Hamilton
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Ross
authors: R
authors: Goodson
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Sophie
authors: S
authors: Jones
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Sarah
authors: S
authors: Eversden
authors: The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors: Peter
authors: P
authors: Davies
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Michael
authors: M
authors: O'Neill
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Michael
authors: M
authors: Hutton
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Philip
authors: P
authors: Szekeres
authors: Lilly Research Centre, Windlesham, Surrey, UK.
authors: Joanna
authors: J
authors: Wolak
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D000073840:Copper-Transporting ATPases / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C054369:MAPT protein, human; D016875:tau Proteins; D020169:Caspases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D019311:Staurosporine
keywords: Alzheimer’s disease; caspases; neurodegenerative diseases; protein aggregation; tau proteins; tauopathies