Myelin pathology: Involvement of molecular chaperones and the promise of chaperonotherapy

The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment

hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions

<p>Abstract</p> <p>Background</p> <p>Hsp70 chaperones are required for key cellular processes and response to environmental changes and survival but they have not been fully characterized yet. The human <it>hsp70</it>-gene family has an unknown number of members (eleven counted over ten years ago); some have been described but the information is incomplete and inconsistent. A coherent body of knowledge encompassing all family components that would facilitate their study individually and as a group is lacking. Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human <it>hsp70 </it>family.</p> <p>Results</p> <p>We identified 47 hsp70 sequences, 17 genes and 30 pseudogenes. The genes distributed into seven evolutionarily distinct groups with distinguishable subgroups according to phylogenetic and other data, such as exon-intron and protein features. The N-terminal ATP-binding domain (ABD) was conserved at least partially in the majority of the proteins but the C-terminal substrate-binding domain (SBD) was not. Nine proteins were typical Hsp70s (65–80 kDa) with ABD and SBD, two were lighter lacking partly or totally the SBD, and six were heavier (>80 kDa) with divergent C-terminal domains. We also analyzed exon-intron features, transcriptional variants and protein structure and isoforms, and modality and patterns of expression in various tissues and developmental stages. Evolutionary analyses, including human <it>hsp70 </it>genes and pseudogenes, and other eukaryotic <it>hsp70 </it>genes, showed that six human genes encoding cytosolic Hsp70s and 27 pseudogenes originated from retro-transposition of HSPA8, a gene highly expressed in most tissues and developmental stages.</p> <p>Conclusion</p> <p>The human <it>hsp70</it>-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8. Human Hsp70 proteins are clustered into seven evolutionary Groups, with divergent C-terminal domains likely defining their distinctive functions. These functions may also be further defined by the observed differences in the N-terminal domain.</p

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks.

In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects

Chaperonin genes on the rise: new divergent classes and intense duplication in human and other vertebrate genomes

<p>Abstract</p> <p>Background</p> <p>Chaperonin proteins are well known for the critical role they play in protein folding and in disease. However, the recent identification of three diverged chaperonin paralogs associated with the human Bardet-Biedl and McKusick-Kaufman Syndromes (BBS and MKKS, respectively) indicates that the eukaryotic chaperonin-gene family is larger and more differentiated than previously thought. The availability of complete genome sequences makes possible a definitive characterization of the complete set of chaperonin sequences in human and other species.</p> <p>Results</p> <p>We identified fifty-four chaperonin-like sequences in the human genome and similar numbers in the genomes of the model organisms mouse and rat. In mammal genomes we identified, besides the well-known CCT chaperonin genes and the three genes associated with the MKKS and BBS pathological conditions, a newly-defined class of chaperonin genes named CCT8L, represented in human by the two sequences CCT8L1 and CCT8L2. Comparative analyses from several vertebrate genomes established the monophyletic origin of chaperonin-like MKKS and BBS genes from the CCT8 lineage. The CCT8L gene originated from a later duplication also in the CCT8 lineage at the onset of mammal evolution and duplicated in primate genomes. The functionality of CCT8L genes in different species was confirmed by evolutionary analyses and in human by expression data. Detailed sequence analysis and structural predictions of MKKS, BBS and CCT8L proteins strongly suggested that they conserve a typical chaperonin-like core structure but that they are unlikely to form a CCT-like oligomeric complex. The characterization of many newly-discovered chaperonin pseudogenes uncovered the intense duplication activity of eukaryotic chaperonin genes.</p> <p>Conclusions</p> <p>In vertebrates, chaperonin genes, driven by intense duplication processes, have diversified into multiple classes and functionalities that extend beyond their well-known protein-folding role as part of the typical oligomeric chaperonin complex, emphasizing previous observations on the involvement of individual CCT monomers in microtubule elongation. The functional characterization of newly identified chaperonin genes will be a challenge for future experimental analyses.</p

Hsp60 expression, new locations, functions, and perspectives for cancer diagnosis and therapy

Hsp60 in eukaryotes is considered typically a mitochondrial chaperone (also called Cpn60) but in the last few years it has become clear that it also occurs in the cytosol, the cell surface, the extracellular space, and in the peripheral blood. Studies with prokaryotic models have shown that Hsp60 plays a role in assisting nascent polypeptides to reach a native conformation, and that it interacts with Hsp10 (which also resides in the mitochondria and is also named Cpn10). In addition to its role in polypeptide folding in association with Hsp10, other functions and interacting molecules have been identified for Hsp60 in the last several years. Some of these newly identified functions are associated with carcinogenesis, specifically with tumor cell survival and proliferation. Thus, assessing the levels of Hsp60 in tumor cells and in sera of cancer patients is becoming an attractive area of investigation aiming at the development of means for practical applications in clinical oncology. Since Hsp60 participates in extracellular molecular interactions and cell signalling and also in key intracellular pathways of some types of tumor cells, the idea of using Hsp60 in anti-cancer therapy (chaperonotherapy) is being investigated. The Hsp could be used either as an anticancer agent alone or in combination with tumor antigens, or as target for anti-chaperone compounds. In this article, a brief review is presented of representative research efforts aimed at assessing Hsp60 in a variety of tumors with the purpose of illustrating possible implications and applications for making early and differential diagnoses, assessing prognosis, monitoring response to treatment, and for developing novel anti-cancer strategies

SARS-CoV-2 in patients with cancer: possible role of mimicry of human molecules by viral proteins and the resulting anti-cancer immunity

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper

Book review "How to Teach English with Technology"

[EN] Gavin Dudeney and Nicky Hockly, How to Teach English with Technology How to... series editor: Jeremy Harmer Harlow: Pearson Longman, 2010, 192 pp ISBN: 978-1-4058-5308-8Siqueira Rocha, JMD. (2011). Book review "How to Teach English with Technology". The EuroCALL Review. 19(0):85-86. https://doi.org/10.4995/eurocall.2011.16275858619

Pure silica nanoparticles for liposome/lipase system encapsulation: Application in biodiesel production

In this work we report the synthesis of organic inorganic solid with spherical morphology where enzyme, as active compounds, is encapsulated. The organic phase of nanospheres is composed of l-phosphatidylcholine, as liposome, and lipase from Rhizomucor miehei, as enzyme. The organic phase is covered with porous inorganic silica shell that could stabilize the internal liposomal phase and, consequently, isolate and protect the bioactive molecules. The liposome and silica amount used during the immobilization procedure have been optimized in order to obtain active and stable heterogeneous biocatalyst. Hybrid-nanospheres containing the enzyme were used to catalyze the transesterification reaction of triolein with methanol to methyl esters, typical biodiesel mixture compounds. The encapsulated enzyme retains its activity after 5 reaction cycles. The total productivity of the best catalyst obtained is higher than that of the free enzyme.The authors, A.C. and U.D., thank the Spanish MICINN (Consolider Ingenio 2010-MULTICAT (CSD2009-00050) and MAT2011-29020-C02-01) for their financial support.Macario, A.; Verri, F.; Díaz Morales, UM.; Corma Canós, A.; Giordano, G. (2013). Pure silica nanoparticles for liposome/lipase system encapsulation: Application in biodiesel production. Catalysis Today. 204:148-155. doi:10.1016/j.cattod.2012.07.014S14815520

The neurochaperonopathies: Anomalies of the chaperone system with pathogenic effects in neurodegenerative and neuromuscular disorders

The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1-Bardet\u2013Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p97 with aberrant post-translational modifications. Awareness of the chaperonopathies as the underlying primary or secondary causes of disease will improve diagnosis and patient management and open the possibility of investigating and developing chaperonotherapy, namely treatment with the abnormal chaperone as the main target. Positive chaperonotherapy would apply in chaperonopathies by defect, i.e., chaperone insufficiency, and consist of chaperone replacement or boosting, whereas negative chaperonotherapy would be pertinent when a chaperone actively participates in the initiation and progression of the disease and must be blocked and eliminated