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Heat shock protein 70 (HSP70) is activated under stress response. Its involvement in cell protection, including energy metabolism and quality control makes it a promising pharmacological target. A strategy to increase HSP70 levels inside the cells is the application of recombinant HSP70. However, cell permeability and functionality of these exogenously applied proteins inside the cells is still disputable. Here, using fluorescence- labeled HSP70, we have studied permeability and distribution of HSP70 inside primary neurons and astrocytes, and how exogenous HSP70 changes mitochondrial metabolism and mitophagy. We have found that exogenous recombinant HSP70 can penetrate the neurons and astrocytes and distributes in mitochondria, lysosomes and in lesser degree in the endoplasmic reticulum. HSP70 increases mitochondrial membrane potential in control neurons and astrocytes, and in fibroblasts of patients with familial Parkinson´s disease (PD) with PINK1 and LRRK2 mutations. Increased mitochondrial membrane potential was associated with higher mitochondrial ROS production and activation of mitophagy. Importantly, preincubation of the cells with HSP70 protected neurons and astrocytes against cell death in a toxic model of PD induced by rotenone, and in the PINK1 and LRRK2 PD human fibroblasts. Thus, exogenous recombinant HSP70 is cell permeable, and acts as endogenous HSP70 protecting cells in the case of toxic model and familial forms of Parkinson's Disease., (© 2024. The Author(s).)

The phenomenon of paramutation describes the interaction between two alleles, in which one allele initiates inherited epigenetic conversion of another allele without affecting the DNA sequence. Epigenetic transformations due to paramutation are accompanied by the change in DNA and/or histone methylation patterns, affecting gene expression. Studies of paramutation in plants and animals have identified small non-coding RNAs as the main effector molecules required for the initiation of epigenetic changes in gene loci. Due to the fact that small non-coding RNAs can be transmitted across generations, the paramutation effect can be inherited and maintained in a population. In this review, we will systematically analyze examples of paramutation in different living systems described so far, highlighting common and different molecular and genetic aspects of paramutation between organisms, and considering the role of this phenomenon in evolution.

After olfactory bulbectomy, animals are often used as a model of major depression or sporadic Alzheimer's disease and, hence, the status of this model is still disputable. To elucidate the nature of alterations in the expression of the genome after the operation, we analyzed transcriptomes of the cortex, hippocampus, and cerebellum of the olfactory bulbectomized (OBX) mice. Analysis of the functional significance of genes in the brain of OBX mice indicates that the balance of the GABA/glutamatergic systems is disturbed with hyperactivation of the latter in the hippocampus, leading to the development of excitotoxicity and induction of apoptosis in the background of severe mitochondrial dysfunction and astrogliosis. On top of this, the synthesis of neurotrophic factors decreases leading to the disruption of the cytoskeleton of neurons, an increase in the level of intracellular calcium, and the activation of tau protein hyperphosphorylation. Moreover, the acetylcholinergic system is deficient in the background of the hyperactivation of acetylcholinesterase. Importantly, the activity of the dopaminergic, endorphin, and opiate systems in OBX mice decreases, leading to hormonal dysfunction. On the other hand, genes responsible for the regulation of circadian rhythms, cell migration, and innate immunity are activated in OBX animals. All this takes place in the background of a drastic downregulation of ribosomal protein genes in the brain. The obtained results indicate that OBX mice represent a model of Alzheimer's disease with elements of major depression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hsp70 is the main molecular chaperone responsible for cellular proteostasis under normal conditions and for restoring the conformation or utilization of proteins damaged by stress. Increased expression of endogenous Hsp70 or administration of exogenous Hsp70 is known to exert neuroprotective effects in models of many neurodegenerative diseases. In this study, we have investigated the effect of exogenous Hsp70 on recovery from peripheral nerve injury in a model of sciatic nerve transection in rats. It was shown that recombinant Hsp70 after being added to the conduit connecting the ends of the nerve at the site of its extended severance, migrates along the nerve into the spinal ganglion and is retained there at least three days. In animals with the addition of recombinant Hsp70 to the conduit, a decrease in apoptosis in the spinal ganglion cells after nerve rupture, an increase in the level of PTEN-induced kinase 1 (PINK1), an increase in markers of nerve tissue regeneration and a decrease in functional deficit were observed compared to control animals. The obtained data indicate the possibility of using recombinant Hsp70 preparations to accelerate the recovery of patients after neurotrauma., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023. Published by Elsevier Inc.)