International Journal of Molecular Sciences

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18 pages, 3274 KiB

Open AccessArticle

The J Domain of Sacsin Disrupts Intermediate Filament Assembly

by Afrooz Dabbaghizadeh, Alexandre Paré, Zacharie Cheng-Boivin, Robin Dagher, Sandra Minotti, Marie-Josée Dicaire, Bernard Brais, Jason C. Young, Heather D. Durham and Benoit J. Gentil

Int. J. Mol. Sci. 2022, 23(24), 15742; https://doi.org/10.3390/ijms232415742 - 12 Dec 2022

Cited by 3 | Viewed by 1570

Abstract

Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate [...] Read more.

Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs^−/− neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured Sacs^−/− motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured Sacs^+/+ fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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14 pages, 1716 KiB

Open AccessArticle

A Combined Cell-Worm Approach to Search for Compounds Counteracting the Toxicity of Tau Oligomers In Vivo

by Carmina Natale, Maria Monica Barzago, Luca Colnaghi, Ada De Luigi, Franca Orsini, Luana Fioriti and Luisa Diomede

Int. J. Mol. Sci. 2022, 23(19), 11277; https://doi.org/10.3390/ijms231911277 - 24 Sep 2022

Cited by 1 | Viewed by 1758

Abstract

A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo, we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were [...] Read more.

A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo, we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days significantly reduced the worm’s locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as a prototype drug. Doxy affected tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and the C. elegans-based approach as a platform for pharmacological screening. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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12 pages, 2802 KiB

Open AccessArticle

Unraveling the Binding Mechanism of Alzheimer’s Drugs with Irisin: Spectroscopic, Calorimetric, and Computational Approaches

by Rashid Waseem, Anas Shamsi, Tanzeel Khan, Md. Imtaiyaz Hassan, Syed Naqui Kazim, Mohammad Shahid and Asimul Islam

Int. J. Mol. Sci. 2022, 23(11), 5965; https://doi.org/10.3390/ijms23115965 - 25 May 2022

Cited by 9 | Viewed by 2057

Abstract

The prevalence of Alzheimer’s disease (AD) has been a major health concern for a long time. Despite recent progress, there is still a strong need to develop effective disease-modifying therapies. Several drugs have already been approved to retard the progression of AD-related symptoms; [...] Read more.

The prevalence of Alzheimer’s disease (AD) has been a major health concern for a long time. Despite recent progress, there is still a strong need to develop effective disease-modifying therapies. Several drugs have already been approved to retard the progression of AD-related symptoms; however, there is a need to develop an effective carrier system for the delivery of drugs to combat such diseases. In recent years, various biological macromolecules, including proteins, have been used as carriers for drug delivery. Irisin is a beneficial hormone in such diseases, including AD and related pathologies. Herein, the interaction mechanism of irisin with AD drugs such as memantine, galantamine, and fluoxetine is investigated. Fluorescence studies revealed that the above drugs bind to irisin with significant affinity, with fluoxetine having the highest binding affinity. Isothermal titration calorimetry (ITC) complemented the spontaneous binding of these drugs with irisin, delineating various associated thermodynamic and binding parameters. Molecular docking further validated the fluorescence and ITC results and unfolded the mechanism that hydrogen bonding governs the binding of fluoxetine to irisin with a significant binding score, i.e., −6.3 kcal/mol. We believe that these findings provide a promising solution to fight against AD as well as a platform for further research to utilize irisin in the drug-delivery system for an effective therapeutic strategy. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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12 pages, 1100 KiB

Open AccessArticle

Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains

by Rosaria Russo, Margherita Romeo, Tim Schulte, Martina Maritan, Luca Oberti, Maria Monica Barzago, Alberto Barbiroli, Carlo Pappone, Luigi Anastasia, Giovanni Palladini, Luisa Diomede and Stefano Ricagno

Int. J. Mol. Sci. 2022, 23(2), 950; https://doi.org/10.3390/ijms23020950 - 16 Jan 2022

Cited by 1 | Viewed by 2076

Abstract

Light chain amyloidosis (AL) is caused by the aberrant overproduction of immunoglobulin light chains (LCs). The resulting abnormally high LC concentrations in blood lead to deposit formation in the heart and other target organs. Organ damage is caused not only by the accumulation [...] Read more.

Light chain amyloidosis (AL) is caused by the aberrant overproduction of immunoglobulin light chains (LCs). The resulting abnormally high LC concentrations in blood lead to deposit formation in the heart and other target organs. Organ damage is caused not only by the accumulation of bulky amyloid deposits, but extensive clinical data indicate that circulating soluble LCs also exert cardiotoxic effects. The nematode C. elegans has been validated to recapitulate LC soluble toxicity in vivo, and in such a model a role for copper ions in increasing LC soluble toxicity has been reported. Here, we applied microscale thermophoresis, isothermal calorimetry and thermal melting to demonstrate the specific binding of Cu²⁺ to the variable domain of amyloidogenic H7 with a sub-micromolar affinity. Histidine residues present in the LC sequence are not involved in the binding, and yet their mutation to Ala reduces the soluble toxicity of H7. Copper ions bind to and destabilize the variable domains and induce a limited stabilization in this domain. In summary, the data reported here, elucidate the biochemical bases of the Cu²⁺-induced toxicity; moreover, they also show that copper binding is just one of the several biochemical traits contributing to LC soluble in vivo toxicity. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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21 pages, 5152 KiB

Open AccessArticle

Rapid Conversion of Amyloid-Beta 1-40 Oligomers to Mature Fibrils through a Self-Catalytic Bimolecular Process

by Bertrand Morel, María P. Carrasco-Jiménez, Samuel Jurado and Francisco Conejero-Lara

Int. J. Mol. Sci. 2021, 22(12), 6370; https://doi.org/10.3390/ijms22126370 - 14 Jun 2021

Cited by 8 | Viewed by 2512

Abstract

The formation of fibrillar aggregates of the amyloid beta peptide (Aβ) in the brain is one of the hallmarks of Alzheimer’s disease (AD). A clear understanding of the different aggregation steps leading to fibrils formation is a keystone in therapeutics discovery. In a [...] Read more.

The formation of fibrillar aggregates of the amyloid beta peptide (Aβ) in the brain is one of the hallmarks of Alzheimer’s disease (AD). A clear understanding of the different aggregation steps leading to fibrils formation is a keystone in therapeutics discovery. In a recent study, we showed that Aβ40 and Aβ42 form dynamic micellar aggregates above certain critical concentrations, which mediate a fast formation of more stable oligomers, which in the case of Aβ40 are able to evolve towards amyloid fibrils. Here, using different biophysical techniques we investigated the role of different fractions of the Aβ aggregation mixture in the nucleation and fibrillation steps. We show that both processes occur through bimolecular interplay between low molecular weight species (monomer and/or dimer) and larger oligomers. Moreover, we report here a novel self-catalytic mechanism of fibrillation of Aβ40, in which early oligomers generate and deliver low molecular weight amyloid nuclei, which then catalyze the rapid conversion of the oligomers to mature amyloid fibrils. This fibrillation catalytic activity is not present in freshly disaggregated low-molecular weight Aβ40 and is, therefore, a property acquired during the aggregation process. In contrast to Aβ40, we did not observe the same self-catalytic fibrillation in Aβ42 spheroidal oligomers, which could neither be induced to fibrillate by the Aβ40 nuclei. Our results reveal clearly that amyloid fibrillation is a multi-component process, in which dynamic collisions between different interacting species favor the kinetics of amyloid nucleation and growth. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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12 pages, 2043 KiB

Open AccessArticle

Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client

by Filipe E. P. Rodrigues, António J. Figueira, Cláudio M. Gomes and Miguel Machuqueiro

Int. J. Mol. Sci. 2021, 22(7), 3629; https://doi.org/10.3390/ijms22073629 - 31 Mar 2021

Cited by 6 | Viewed by 4727

Abstract

S100B is an astrocytic extracellular Ca²⁺-binding protein implicated in Alzheimer’s disease, whose role as a holdase-type chaperone delaying Aβ₄₂ aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the [...] Read more.

S100B is an astrocytic extracellular Ca²⁺-binding protein implicated in Alzheimer’s disease, whose role as a holdase-type chaperone delaying Aβ₄₂ aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aβ₄₂. Driven by previous structural data, we used the Aβ_25–35 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length Aβ using long (1 μs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, Aβ-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(Aβ)/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over Aβ aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the Aβ-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer’s disease. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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12 pages, 1383 KiB

Open AccessArticle

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

by Vincenzo Antona, Federica Scalia, Elisa Giorgio, Francesca C. Radio, Alfredo Brusco, Massimiliano Oliveri, Giovanni Corsello, Fabrizio Lo Celso, Maria Vadalà, Everly Conway de Macario, Alberto J. L. Macario, Francesco Cappello and Mario Giuffrè

Int. J. Mol. Sci. 2020, 21(20), 7631; https://doi.org/10.3390/ijms21207631 - 15 Oct 2020

Cited by 9 | Viewed by 3364

Abstract

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) [...] Read more.

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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18 pages, 2091 KiB

Open AccessArticle

Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

by Yusuke Yamashita, Shuhei Morita, Hiroki Hosoi, Hiroshi Kobata, Shohei Kishimoto, Tatsuya Ishibashi, Hiroyuki Mishima, Akira Kinoshita, Bradley J. Backes, Koh-Ichiro Yoshiura, Feroz R. Papa, Takashi Sonoki and Shinobu Tamura

Int. J. Mol. Sci. 2020, 21(17), 6314; https://doi.org/10.3390/ijms21176314 - 31 Aug 2020

Cited by 8 | Viewed by 3145

Abstract

Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the ‘mono’-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping [...] Read more.

Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the ‘mono’-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear. Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM. Results: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM. Conclusion: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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Review

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10 pages, 889 KiB

Open AccessReview

A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)

by Alejandra Gonzalez-Duarte and Alfredo Ulloa-Aguirre

Int. J. Mol. Sci. 2021, 22(23), 13158; https://doi.org/10.3390/ijms222313158 - 06 Dec 2021

Cited by 11 | Viewed by 3387

Abstract

Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes [...] Read more.

Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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24 pages, 26884 KiB

Open AccessReview

Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

by Alfredo Ulloa-Aguirre, Teresa Zariñán and Eduardo Jardón-Valadez

Int. J. Mol. Sci. 2021, 22(22), 12329; https://doi.org/10.3390/ijms222212329 - 15 Nov 2021

Cited by 4 | Viewed by 2573

Abstract

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric [...] Read more.

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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20 pages, 1343 KiB

Open AccessReview

Understanding the Role of Protein Glycation in the Amyloid Aggregation Process

by Ivana Sirangelo and Clara Iannuzzi

Int. J. Mol. Sci. 2021, 22(12), 6609; https://doi.org/10.3390/ijms22126609 - 21 Jun 2021

Cited by 32 | Viewed by 3859

Abstract

Protein function and flexibility is directly related to the native distribution of its structural elements and any alteration in protein architecture leads to several abnormalities and accumulation of misfolded proteins. This phenomenon is associated with a range of increasingly common human disorders, including [...] Read more.

Protein function and flexibility is directly related to the native distribution of its structural elements and any alteration in protein architecture leads to several abnormalities and accumulation of misfolded proteins. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidosis characterized by the accumulation of amyloid aggregates both in the extracellular space of tissues and as intracellular deposits. Post-translational modifications are known to have an active role in the in vivo amyloid aggregation as able to affect protein structure and dynamics. Among them, a key role seems to be played by non-enzymatic glycation, the most unwanted irreversible modification of the protein structure, which strongly affects long-living proteins throughout the body. This study provided an overview of the molecular effects induced by glycation on the amyloid aggregation process of several protein models associated with misfolding diseases. In particular, we analyzed the role of glycation on protein folding, kinetics of amyloid formation, and amyloid cytotoxicity in order to shed light on the role of this post-translational modification in the in vivo amyloid aggregation process. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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25 pages, 1627 KiB

Open AccessReview

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

by Helene J. Bustad, Juha P. Kallio, Marta Vorland, Valeria Fiorentino, Sverre Sandberg, Caroline Schmitt, Aasne K. Aarsand and Aurora Martinez

Int. J. Mol. Sci. 2021, 22(2), 675; https://doi.org/10.3390/ijms22020675 - 12 Jan 2021

Cited by 26 | Viewed by 8664

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such [...] Read more.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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14 pages, 636 KiB

Open AccessReview

Ferroptosis-Related Flavoproteins: Their Function and Stability

by R. Martin Vabulas

Int. J. Mol. Sci. 2021, 22(1), 430; https://doi.org/10.3390/ijms22010430 - 04 Jan 2021

Cited by 11 | Viewed by 3658

Abstract

Ferroptosis has been described recently as an iron-dependent cell death driven by peroxidation of membrane lipids. It is involved in the pathogenesis of a number of diverse diseases. From the other side, the induction of ferroptosis can be used to kill tumor cells [...] Read more.

Ferroptosis has been described recently as an iron-dependent cell death driven by peroxidation of membrane lipids. It is involved in the pathogenesis of a number of diverse diseases. From the other side, the induction of ferroptosis can be used to kill tumor cells as a novel therapeutic approach. Because of the broad clinical relevance, a comprehensive understanding of the ferroptosis-controlling protein network is necessary. Noteworthy, several proteins from this network are flavoenzymes. This review is an attempt to present the ferroptosis-related flavoproteins in light of their involvement in anti-ferroptotic and pro-ferroptotic roles. When available, the data on the structural stability of mutants and cofactor-free apoenzymes are discussed. The stability of the flavoproteins could be an important component of the cellular death processes. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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49 pages, 1947 KiB

Open AccessReview

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

by M. Catarina Silva and Stephen J. Haggarty

Int. J. Mol. Sci. 2020, 21(23), 8948; https://doi.org/10.3390/ijms21238948 - 25 Nov 2020

Cited by 46 | Viewed by 7688

Abstract

Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) [...] Read more.

Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed. Full article

(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)

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