Abstract
Misfolding, aggregation and accumulation of proteins are toxic elements in the progression of a broad range of neurodegenerative diseases. Molecular chaperones enable a cellular defense by reducing or compartmentalizing these insults. Small heat shock proteins (sHsps) engage proteins early in the process of misfolding and can facilitate their proper folding or refolding, sequestration, or clearance. Here, we evaluate the effects of the sHsp Hsp22, as well as a pseudophosphorylated mutant and an N-terminal domain deletion (NTDΔ) variant on tau aggregation in vitro and tau accumulation and aggregation in cultured cells. Hsp22 wild-type (WT) protein had a significant inhibitory effect on heparin-induced aggregation in vitro and the pseudophosphorylated mutant Hsp22 demonstrated a similar effect. When co-expressed in a cell culture model with tau, these Hsp22 constructs significantly reduced soluble tau protein levels when transfected at a high ratio relative to tau. However, the Hsp22 NTDΔ protein drastically reduced the soluble protein expression levels of both tau WT and tau P301L/S320F even at lower transfection ratios, which resulted in a correlative reduction of the triton-insoluble tau P301L/S320F aggregates.
Highlights
Maintenance of cellular proteostasis is critically important for cellular function and survival [1,2,3], especially in neurons [4,5,6]
Previous work has shown that certain molecular chaperones, including a Small heat shock proteins (sHsps) (Hsp27), can interact with tau protein and inhibit or delay aggregation [26,28]
We evaluated the effects of Hsp22 WT, a pseudophosphorylated mutant (S/D), and a mutation with non-polar residues (S/A) on tau aggregation in vitro
Summary
Maintenance of cellular proteostasis is critically important for cellular function and survival [1,2,3], especially in neurons [4,5,6]. Misfolding, aggregation and disrupted protein clearance contribute to an imbalance in proteostasis that can foster the accumulation of toxic protein aggregates [6,7,8]. Aberrant accumulation of aggregated protein is often associated with neurodegenerative disease progression [9,10,11]. Molecular chaperones can counteract this proteostatic imbalance by facilitating proper folding or refolding, sequestration, or clearance of misfolded proteins [14,15,16,17,18]. Small heat shock proteins (sHsps) are a class of ATP-independent molecular chaperones that associate with early misfolded proteins and sequester these aggregation-prone intermediates for processing by ATP-dependent molecular chaperone complexes that include the 70 kDa heat shock protein (Hsp70), the 90 kDa heat shock protein (Hsp90) [19,20], or other protein clearance machinery. Small heat shock proteins (sHsps) are a class of ATP-independent molecular chaperones that associate with early misfolded proteins and sequester these aggregation-prone intermediates for processing by ATP-dependent molecular chaperone complexes that include the 70 kDa heat shock protein (Hsp70), the 90 kDa heat shock protein (Hsp90) [19,20], or other protein clearance machinery. sHsps canonically contain a conserved core α-crystallin domain (ACD) flanked by variable flexible N-terminal and C-terminal domains (NTD and CTD) [21,22]. sHsps form dimers through an interface between ACDs. sHsps further multimerize to form higher order dynamic oligomers via interactions of an IXI/V sequence in the CTD with a hydrophobic groove formed by the β4 and β8 strands of the ACD, as well as through complex interactions of the NTD with neighboring sHsp subunits [23,24]
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