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 (3ϫS/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 3ϫS/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 3ϫS/D Hsp27. Because the 3ϫS/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.

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

“…We used dynamic light scattering (DLS) to assess how the Hsp90/FKBP51 complex was regulating the kinetics of global tau aggregation (44). For these studies, tau aggregation was induced with heparin sulfate in the presence of Hsp90 or FKBP51 alone and in the presence of Hsp90 and FKBP51 together.…”

“…FKBP51 expression was observed in the HPC; however, the AAV did not transduce all neurons ( Figure 4A). Due to this typical limitation of AAV use, a fluorescent masking technique previously developed by our lab was used to evaluate the levels of tau in neurons express- ing the AAV product, in this case FKBP51 or GFP (44). Triple-immunofluorescent staining of sections for FKBP51, total tau, and the neuronal marker, NeuN, revealed that the amount of tau found within FKBP51-positive neurons was significantly increased compared with tau levels in neurons overexpressing GFP (Figure 4, B and C).…”

HSPA1A-Independent Suppression of PARK2 C289G Protein Aggregation by Human Small Heat Shock Proteins

“…Until now, HSPB1, HSPB5, and HSPB8 have been the most widely studied members. They have been found to reduce protein aggregates caused by proteins containing an expanded polyQ tract (HSPB8 [20]), tau (HSPB1 [34][35][36]), amyloid-beta (HSPB1, HSPB5, and HSPB8 [37,38]), TDP43 (HSPB8 [15]) and SOD1 (HSPB1, HSPB5, and HSPB8 [18,39]). However, only little is known about were treated with bortezomib (100 nM) or with 3-MA (20 mM) and wortmannin (200 nM) overnight.…”

Glucose-regulated Protein 94 Triage of Mutant Myocilin through Endoplasmic Reticulum-associated Degradation Subverts a More Efficient Autophagic Clearance Mechanism

“…Quantification and Statistical Analyses-Quantification of all blots was performed using ImageJ software as described previously (30). Graphs are plotted based on relative intensity values.…”