title: Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice.
abstract: Molecular chaperones regulate the aggregation of a number of proteins that pathologically misfold and accumulate in neurodegenerative diseases. Identifying ways to manipulate these proteins in disease models is an area of intense investigation; however, the translation of these results to the mammalian brain has progressed more slowly. In this study, we investigated the ability of one of these chaperones, heat shock protein 27 (Hsp27), to modulate tau dynamics. Recombinant wild-type Hsp27 and a genetically altered version of Hsp27 that is perpetually pseudo-phosphorylated (3×S/D) were generated. Both Hsp27 variants interacted with tau, and atomic force microscopy and dynamic light scattering showed that both variants also prevented tau filament formation. However, extrinsic genetic delivery of these two Hsp27 variants to tau transgenic mice using adeno-associated viral particles showed that wild-type Hsp27 reduced neuronal tau levels, whereas 3×S/D Hsp27 was associated with increased tau levels. Moreover, rapid decay in hippocampal long-term potentiation (LTP) intrinsic to this tau transgenic model was rescued by wild-type Hsp27 overexpression but not by 3×S/D Hsp27. Because the 3×S/D Hsp27 mutant cannot cycle between phosphorylated and dephosphorylated states, we can conclude that Hsp27 must be functionally dynamic to facilitate tau clearance from the brain and rescue LTP; however, when this property is compromised, Hsp27 may actually facilitate accumulation of soluble tau intermediates.
authors.affiliation: Department of Molecular Medicine, University of South Florida Health Byrd Alzheimer's Institute, Tampa, Florida 33613, USA.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Hill
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jones
authors.forename: Clara
authors.initials: C
authors.lastname: Kraft
authors.forename: Justin
authors.initials: J
authors.lastname: Rogers
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Lisa
authors.initials: L
authors.lastname: Lawson
authors.forename: Amelia G
authors.initials: AG
authors.lastname: Johnson
authors.forename: Donna
authors.initials: D
authors.lastname: Wilcock
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.forename: Martin
authors.initials: M
authors.lastname: Muschol
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Jessica
authors.initials: J
authors.lastname: Banko
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000818:Animals; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D009473:Neuronal Plasticity / Q000235:genetics*; D010766:Phosphorylation / Q000502:physiology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D016875:tau Proteins