Small Heat Shock Protein 22 Improves Cognition and Learning in the Tauopathic Brain

The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.

Heat Shock Protein 22 in Physiological and Pathological Hearts: Small Molecule, Large Potentials

Small heat shock protein 22 (HSP22) belongs to the superfamily of heat shock proteins and is predominantly expressed in the heart, brain, skeletal muscle, and different types of cancers. It has been found that HSP22 is involved in variant cellular functions in cardiomyocytes and plays a vital role in cardiac protection against cardiomyocyte injury under diverse stress. This review summarizes the multiple functions of HSP22 in the heart and the underlying molecular mechanisms through modulating gene transcription, post-translational modification, subcellular translocation of its interacting proteins, and protein degradation, facilitating mitochondrial function, cardiac metabolism, autophagy, and ROS production and antiapoptotic effect. We also discuss the association of HSP22 in cardiac pathologies, including human dilated cardiomyopathy, pressure overload-induced heart failure, ischemic heart diseases, and aging-related cardiac metabolism disorder. The collected information would provide insights into the understanding of the HSP22 in heart diseases and lead to discovering the therapeutic targets.

Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response

Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown. In this study, we used an Hsp22 knockout (KO) mouse model to determine whether loss of Hsp22 impairs cardiac growth and function with increasing age under physiological conditions. Cardiac structural and functional alterations at baseline were measured using echocardiography and invasive catheterization in Hsp22 KO mice during aging transition compared to their age-matched wild-type (WT) littermates. Our results showed that Hsp22 deletion induced progressive cardiac dilation along with declined function during the aging transition. Mechanistically, the loss of Hsp22 impaired BCL-2–associated athanogene 3 (BAG3) expression and its associated cardiac autophagy, undermined cardiac energy metabolism homeostasis and increased oxidative damage. This study showed that Hsp22 played an essential role in the non-stressed heart during the early stage of aging, which may bring new insight into understanding the pathogenesis of age-related dilated cardiomyopathy.