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Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 19538

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Prof. Dr. Michael Ugrumov

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1. Faculty of Psychology, National Research University “Higher School of Economy”, Moscow, Russia
2. Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia
Interests: developmental neurobiology; neuroendocrinology; neurodegenerative diseases; Parkinson’s disease; preclinical diagnosis; preventive neuroprotective therapy
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Dear Colleagues,

The fight against neurodegenerative diseases (NDDs), such as Alzheimer's disease and Parkinson's disease, is a global challenge of the 21st century since these diseases lead to disability and death. This is due to late diagnosis and treatment that begins many years after the onset of the disease, at the loss of most specific neurons and depletion of neuroplasticity. Therefore, priorities in neuroscience include fundamental studies of the cellular and molecular mechanisms of early pathogenesis of NDDs and their peripheral manifestations targeting early diagnosis and preventive treatment. Modeling the progression of NDDs in animals is the only means we currently have to study the molecular mechanisms of neurodegeneration and neuroplasticity in the central and peripheral nervous system at the early stage of the disease. In turn, studies of early peripheral genetic and metabolic manifestations of NDDs are carried out not only in animal models, but also in humans—at the prodromal stage, diagnosed by early nonspecific symptoms, and at the early clinical stage, after the appearance of specific symptoms. Most of these studies are focused on changes in the chemical composition of bodily fluids (CSF, plasma, etc.), as well as changes in gene expression and the phenotype of peripheral cells (blood cells, skin cells, etc.). These findings are considered to be biochemical and biomolecular manifestations of the pathogenesis of NDDs and potential diagnostic markers. Fundamental knowledge of the cellular and molecular mechanisms underlying NDDs and the development of methods for early diagnosis may open up prospects for the use of preventive neuroprotective treatments that could slow down neurodegeneration and prolong the period of physical and social activity of subjects at risk.

Prof. Dr. Michael Ugrumov
Guest Editor

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Keywords

neurodegenerative diseases
Alzheimer's disease
Parkinson’s disease
pathogenesis
animal models
molecular mechanisms
biomarkers
early diagnosis
preventive treatment

Published Papers (6 papers)

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Research

16 pages, 26620 KiB

Open AccessArticle

APEX2-Mediated Proximity Labeling Resolves the DDIT4-Interacting Proteome

by Marianna Naki, Olga Gourdomichali, Katerina Zonke, Fedon-Giasin Kattan, Manousos Makridakis, Georgia Kontostathi, Antonia Vlahou and Epaminondas Doxakis

Int. J. Mol. Sci. 2022, 23(9), 5189; https://doi.org/10.3390/ijms23095189 - 6 May 2022

Cited by 2 | Viewed by 4196

Abstract

DNA damage-inducible transcript 4 (DDIT4) is a ubiquitous protein whose expression is transiently increased in response to various stressors. Chronic expression has been linked to various pathologies, including neurodegeneration, inflammation, and cancer. DDIT4 is best recognized for repressing mTORC1, an essential protein complex activated by nutrients and hormones. Accordingly, DDIT4 regulates metabolism, oxidative stress, hypoxic survival, and apoptosis. Despite these well-defined biological functions, little is known about its interacting partners and their unique molecular functions. Here, fusing an enhanced ascorbate peroxidase 2 (APEX2) biotin-labeling enzyme to DDIT4 combined with mass spectrometry, the proteins in the immediate vicinity of DDIT4 in either unstressed or acute stress conditions were identified in situ. The context-dependent interacting proteomes were quantitatively but not functionally distinct. DDIT4 had twice the number of interaction partners during acute stress compared to unstressed conditions, and while the two protein lists had minimal overlap in terms of identity, the proteins’ molecular function and classification were essentially identical. Moonlighting keratins and ribosomal proteins dominated the proteomes in both unstressed and stressed conditions, with many of their members having established non-canonical and indispensable roles during stress. Multiple keratins regulate mTORC1 signaling via the recruitment of 14-3-3 proteins, whereas ribosomal proteins control translation, cell cycle progression, DNA repair, and death by sequestering critical proteins. In summary, two potentially distinct mechanisms of DDIT4 molecular function have been identified, paving the way for additional research to confirm and consolidate these findings. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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27 pages, 4058 KiB

Open AccessArticle

A New Method for the Visualization of Living Dopaminergic Neurons and Prospects for Using It to Develop Targeted Drug Delivery to These Cells

by Victor Blokhin, Alina V. Lavrova, Sergey A. Surkov, Eduard R. Mingazov, Natalia M. Gretskaya, Vladimir V. Bezuglov and Michael V. Ugrumov

Int. J. Mol. Sci. 2022, 23(7), 3678; https://doi.org/10.3390/ijms23073678 - 27 Mar 2022

Cited by 2 | Viewed by 4835

Abstract

This is the first study aiming to develop a method for the long-term visualization of living nigrostriatal dopaminergic neurons using 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine-BODIPY (GBR-BP), the original fluorescent substance, which is a derivative of GBR-12909, a dopamine uptake inhibitor. This method is based on the authors’ hypothesis about the possibility of specifically internalizing into dopaminergic neurons substances with a high affinity for the dopamine transporter (DAT). Using a culture of mouse embryonic mesencephalic and LUHMES cells (human embryonic mesencephalic cells), as well as slices of the substantia nigra of adult mice, we have obtained evidence that GBR-BP is internalized specifically into dopaminergic neurons in association with DAT via a clathrin-dependent mechanism. Moreover, GBR-BP has been proven to be nontoxic. As we have shown in a primary culture of mouse metencephalon, GBR-BP is also specifically internalized into some noradrenergic and serotonergic neurons, but is not delivered to nonmonoaminergic neurons. Our data hold great promise for visualization of dopaminergic neurons in a mixed cell population to study their functioning, and can also be considered a new approach for the development of targeted drug delivery to dopaminergic neurons in pathology, including Parkinson’s disease. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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11 pages, 1451 KiB

Open AccessArticle

GFP–Margatoxin, a Genetically Encoded Fluorescent Ligand to Probe Affinity of Kv1.3 Channel Blockers

by Kristina R. Denisova, Nikita A. Orlov, Sergey A. Yakimov, Elena A. Kryukova, Dmitry A. Dolgikh, Mikhail P. Kirpichnikov, Alexey V. Feofanov and Oksana V. Nekrasova

Int. J. Mol. Sci. 2022, 23(3), 1724; https://doi.org/10.3390/ijms23031724 - 2 Feb 2022

Cited by 6 | Viewed by 1819

Abstract

Peptide pore blockers and their fluorescent derivatives are useful molecular probes to study the structure and functions of the voltage-gated potassium Kv1.3 channel, which is considered as a pharmacological target in the treatment of autoimmune and neurological disorders. We present Kv1.3 fluorescent ligand, GFP–MgTx, constructed on the basis of green fluorescent protein (GFP) and margatoxin (MgTx), the peptide, which is widely used in physiological studies of Kv1.3. Expression of the fluorescent ligand in E. coli cells resulted in correctly folded and functionally active GFP–MgTx with a yield of 30 mg per 1 L of culture. Complex of GFP–MgTx with the Kv1.3 binding site is reported to have the dissociation constant of 11 ± 2 nM. GFP–MgTx as a component of an analytical system based on the hybrid KcsA–Kv1.3 channel is shown to be applicable to recognize Kv1.3 pore blockers of peptide origin and to evaluate their affinities to Kv1.3. GFP–MgTx can be used in screening and pre-selection of Kv1.3 channel blockers as potential drug candidates. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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12 pages, 1955 KiB

Open AccessArticle

Water-Soluble Products of Photooxidative Destruction of the Bisretinoid A2E Cause Proteins Modification in the Dark

by Alexander Dontsov, Marina Yakovleva, Natalia Trofimova, Natalia Sakina, Alexander Gulin, Arseny Aybush, Fedor Gostev, Alexander Vasin, Tatiana Feldman and Mikhail Ostrovsky

Int. J. Mol. Sci. 2022, 23(3), 1534; https://doi.org/10.3390/ijms23031534 - 28 Jan 2022

Cited by 6 | Viewed by 2409

Abstract

Aging of the retina is accompanied by a sharp increase in the content of lipofuscin granules and bisretinoid A2E in the cells of the retinal pigment epithelium (RPE) of the human eye. It is known that A2E can have a toxic effect on RPE cells. However, the specific mechanisms of the toxic effect of A2E are poorly understood. We investigated the effect of the products of photooxidative destruction of A2E on the modification of bovine serum albumin (BSA) and hemoglobin from bovine erythrocytes. A2E was irradiated with a blue light-emitting diode (LED) source (450 nm) or full visible light (400–700 nm) of a halogen lamp, and the resulting water-soluble products of photooxidative destruction were investigated for the content of carbonyl compounds by mass spectrometry and reaction with thiobarbituric acid. It has been shown that water-soluble products formed during A2E photooxidation and containing carbonyl compounds cause modification of serum albumin and hemoglobin, measured by an increase in fluorescence intensity at 440–455 nm. The antiglycation agent aminoguanidine inhibited the process of modification of proteins. It is assumed that water-soluble carbonyl products formed as a result of A2E photodestruction led to the formation of modified proteins, activation of the inflammation process, and, as a consequence, to the progression of various senile eye pathologies. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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15 pages, 2468 KiB

Open AccessArticle

Lipofuscin Granule Bisretinoid Oxidation in the Human Retinal Pigment Epithelium forms Cytotoxic Carbonyls

by Marina Yakovleva, Alexander Dontsov, Natalia Trofimova, Natalia Sakina, Alexey Kononikhin, Arseny Aybush, Alexander Gulin, Tatiana Feldman and Mikhail Ostrovsky

Int. J. Mol. Sci. 2022, 23(1), 222; https://doi.org/10.3390/ijms23010222 - 25 Dec 2021

Cited by 11 | Viewed by 2904

Abstract

Age-related macular degeneration (AMD) is the primary cause of central blindness among the elderly. AMD is associated with progressive accumulation of lipofuscin granules in retinal pigment epithelium (RPE) cells. Lipofuscin contains bisretinoid fluorophores, which are photosensitizers and are phototoxic to RPE and neuroretinal cells. In the presence of oxygen, bisretinoids are also oxidized, forming various products, consisting primarily of aldehydes and ketones, which are also potentially cytotoxic. In a prior study, we identified that in AMD, bisretinoid oxidation products are increased in RPE lipofuscin granules. The purpose of the present study was to determine if these products were toxic to cellular structures. The physicochemical characteristics of bisretinoid oxidation products in lipofuscin, which were obtained from healthy donor eyes, were studied. Raman spectroscopy and time-of-flight secondary ion mass spectrometry (ToF–SIMS) analysis identified the presence of free-state aldehydes and ketones within the lipofuscin granules. Together, fluorescence spectroscopy, high-performance liquid chromatography, and mass spectrometry revealed that bisretinoid oxidation products have both hydrophilic and amphiphilic properties, allowing their diffusion through lipofuscin granule membrane into the RPE cell cytoplasm. These products contain cytotoxic carbonyls, which can modify cellular proteins and lipids. Therefore, bisretinoid oxidation products are a likely aggravating factor in the pathogenesis of AMD. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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15 pages, 1773 KiB

Open AccessArticle

The Dynamics of β-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer’s Disease

by Anna E. Bugrova, Polina A. Strelnikova, Maria I. Indeykina, Alexey S. Kononikhin, Natalia V. Zakharova, Alexander G. Brzhozovskiy, Evgeny P. Barykin, Stanislav I. Pekov, Maria S. Gavrish, Alexey A. Babaev, Anna M. Kosyreva, Anna Y. Morozova, Daniil A. Degterev, Vladimir A. Mitkevich, Igor A. Popov, Alexander A. Makarov and Evgeny N. Nikolaev

Int. J. Mol. Sci. 2022, 23(1), 27; https://doi.org/10.3390/ijms23010027 - 21 Dec 2021

Cited by 5 | Viewed by 2651

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia among the elderly. Neuropathologically, AD is characterized by the deposition of a 39- to 42-amino acid long β-amyloid (Aβ) peptide in the form of senile plaques. Several post-translational modifications (PTMs) in the N-terminal domain have been shown to increase the aggregation and cytotoxicity of Aβ, and specific Aβ proteoforms (e.g., Aβ with isomerized D7 (isoD7-Aβ)) are abundant in the senile plaques of AD patients. Animal models are indispensable tools for the study of disease pathogenesis, as well as preclinical testing. In the presented work, the accumulation dynamics of Aβ proteoforms in the brain of one of the most widely used amyloid-based mouse models (the 5xFAD line) was monitored. Mass spectrometry (MS) approaches, based on ion mobility separation and the characteristic fragment ion formation, were applied. The results indicated a gradual increase in the Aβ fraction of isoD7-Aβ, starting from approximately 8% at 7 months to approximately 30% by 23 months of age. Other specific PTMs, in particular, pyroglutamylation, deamidation, and oxidation, as well as phosphorylation, were also monitored. The results for mice of different ages demonstrated that the accumulation of Aβ proteoforms correlate with the formation of Aβ deposits. Although the mouse model cannot be a complete analogue of the processes occurring in the human brain in AD, and several of the observed parameters differ significantly from human values supposedly due to the limited lifespan of the model animals, this dynamic study provides evidence on at least one of the possible mechanisms that can trigger amyloidosis in AD, i.e., the hypothesis on the relationship between the accumulation of isoD7-Aβ and the progression of AD-like pathology. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Diagnosis and Treatment)

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