Biomedicines

Editorial

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Open AccessEditorial

Editorial of the Special Issue: Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease

by Natalia Ninkina and Michail S. Kukharsky

Biomedicines 2023, 11(9), 2330; https://doi.org/10.3390/biomedicines11092330 - 22 Aug 2023

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Abstract

Extensive studies of α-synuclein function and dysfunction revealed its involvement in multiple normal and aberrant molecular processes and, consequently, numerous and diverse effects on the neuronal cell biology [...] Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

Research

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16 pages, 3000 KiB

Open AccessArticle

Brain Degeneration in Synucleinopathies Based on Analysis of Cognition and Other Nonmotor Features: A Multimodal Imaging Study

by Olaia Lucas-Jiménez, Naroa Ibarretxe-Bilbao, Ibai Diez, Javier Peña, Beatriz Tijero, Marta Galdós, Ane Murueta-Goyena, Rocío Del Pino, Marian Acera, Juan Carlos Gómez-Esteban, Iñigo Gabilondo and Natalia Ojeda

Biomedicines 2023, 11(2), 573; https://doi.org/10.3390/biomedicines11020573 - 15 Feb 2023

Cited by 1 | Viewed by 1443

Abstract

Background: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. Methods: Sixty-two patients (n = 6 E46K-SNCA, n [...] Read more.

Background: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. Methods: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson’s disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients’ samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. Results: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. Conclusions: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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17 pages, 2812 KiB

Open AccessArticle

Does the SARS-CoV-2 Spike Receptor-Binding Domain Hamper the Amyloid Transformation of Alpha-Synuclein after All?

by Yulia Stroylova, Anastasiia Konstantinova, Victor Stroylov, Ivan Katrukha, Fedor Rozov and Vladimir Muronetz

Biomedicines 2023, 11(2), 498; https://doi.org/10.3390/biomedicines11020498 - 09 Feb 2023

Cited by 3 | Viewed by 1721

Abstract

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our [...] Read more.

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our work was to analyze the effect of the receptor-binding domain of the coronavirus S-protein domain (RBD) on alpha-synuclein amyloid aggregation. Molecular modeling showed that the predicted RBD complex with monomeric alpha-synuclein is stable over 100 ns of molecular dynamics. Analysis of the interactions of RBD with the amyloid form of alpha-synuclein showed that during molecular dynamics for 200 ns the number of contacts is markedly higher than that for the monomeric form. The formation of the RBD complex with the alpha-synuclein monomer was confirmed immunochemically by immobilization of RBD on its specific receptor ACE2. Changes in the spectral characteristics of the intrinsic tryptophans of RBD and hydrophobic dye ANS indicate an interaction between the monomeric proteins, but according to the data of circular dichroism spectra, this interaction does not lead to a change in their secondary structure. Data on the kinetics of amyloid fibril formation using several spectral approaches strongly suggest that RBD prevents the amyloid transformation of alpha-synuclein. Moreover, the fibrils obtained in the presence of RBD showed significantly less cytotoxicity on SH-SY5Y neuroblastoma cells. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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11 pages, 1535 KiB

Open AccessArticle

Gamma-Synuclein Dysfunction Causes Autoantibody Formation in Glaucoma Patients and Dysregulation of Intraocular Pressure in Mice

by Tatiana A. Pavlenko, Andrei Y. Roman, Olga A. Lytkina, Nadezhda E. Pukaeva, Martha W. Everett, Iuliia S. Sukhanova, Vladislav O. Soldatov, Nina G. Davidova, Natalia B. Chesnokova, Ruslan K. Ovchinnikov and Michail S. Kukharsky

Biomedicines 2023, 11(1), 60; https://doi.org/10.3390/biomedicines11010060 - 27 Dec 2022

Cited by 2 | Viewed by 1988

Abstract

Dysregulation of intraocular pressure (IOP) is one of the main risk factors for glaucoma. γ-synuclein is a member of the synuclein family of widely expressed synaptic proteins within the central nervous system that are implicated in certain types of neurodegeneration. γ-synuclein expression and [...] Read more.

Dysregulation of intraocular pressure (IOP) is one of the main risk factors for glaucoma. γ-synuclein is a member of the synuclein family of widely expressed synaptic proteins within the central nervous system that are implicated in certain types of neurodegeneration. γ-synuclein expression and localization changes in the retina and optic nerve of patients with glaucoma. However, the mechanisms by which γ-synuclein could contribute to glaucoma are poorly understood. We assessed the presence of autoantibodies to γ-synuclein in the blood serum of patients with primary open-angle glaucoma (POAG) by immunoblotting. A positive reaction was detected for five out of 25 patients (20%) with POAG. Autoantibodies to γ-synuclein were not detected in a group of patients without glaucoma. We studied the dynamics of IOP in response to IOP regulators in knockout mice (γ-KO) to understand a possible link between γ-synuclein dysfunction and glaucoma-related pathophysiological changes. The most prominent decrease of IOP in γ-KO mice was observed after the instillation of 1% phenylephrine and 10% dopamine. The total protein concentration in tear fluid of γ-KO mice was approximately two times higher than that of wild-type mice, and the activity of neurodegeneration-linked protein α2-macroglobulin was reduced. Therefore, γ-synuclein dysfunction contributes to pathological processes in glaucoma, including dysregulation of IOP. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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20 pages, 4792 KiB

Open AccessArticle

Loss of the Synuclein Family Members Differentially Affects Baseline- and Apomorphine-Associated EEG Determinants in Single-, Double- and Triple-Knockout Mice

by Vasily Vorobyov, Alexander Deev, Iuliia Sukhanova, Olga Morozova, Zoya Oganesyan, Kirill Chaprov and Vladimir L. Buchman

Biomedicines 2022, 10(12), 3128; https://doi.org/10.3390/biomedicines10123128 - 04 Dec 2022

Cited by 3 | Viewed by 1603

Abstract

Synucleins comprise a family of small proteins highly expressed in the nervous system of vertebrates and involved in various intraneuronal processes. The malfunction of alpha-synuclein is one of the key events in pathogenesis of Parkinson disease and certain other neurodegenerative diseases, and there [...] Read more.

Synucleins comprise a family of small proteins highly expressed in the nervous system of vertebrates and involved in various intraneuronal processes. The malfunction of alpha-synuclein is one of the key events in pathogenesis of Parkinson disease and certain other neurodegenerative diseases, and there is a growing body of evidence that malfunction of other two synucleins might be involved in pathological processes in the nervous system. The modulation of various presynaptic mechanisms of neurotransmission is an important function of synucleins, and therefore, it is feasible that their deficiency might affect global electrical activity detected of the brain. However, the effects of the loss of synucleins on the frequency spectra of electroencephalograms (EEGs) have not been systematically studied so far. In the current study, we assessed changes in such spectra in single-, double- and triple-knockout mice lacking alpha-, beta- and gamma-synucleins in all possible combinations. EEGs were recorded from the motor cortex, the putamen, the ventral tegmental area and the substantia nigra of 78 3-month-old male mice from seven knockout groups maintained on the C57BL/6J genetic background, and 10 wild-type C57BL/6J mice for 30 min before and for 60 min after the systemic injection of a DA receptor agonist, apomorphine (APO). We found that almost any variant of synuclein deficiency causes multiple changes in both basal and APO-induced EEG oscillation profiles. Therefore, it is not the absence of any particular synuclein but rather a disbalance of synucleins that causes widespread changes in EEG spectral profiles. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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13 pages, 1089 KiB

Open AccessArticle

by Viktor S. Kokhan, Kirill Chaprov, Natalia N. Ninkina, Petr K. Anokhin, Ekaterina P. Pakhlova, Natalia Y. Sarycheva and Inna Y. Shamakina

Biomedicines 2022, 10(9), 2163; https://doi.org/10.3390/biomedicines10092163 - 02 Sep 2022

Cited by 3 | Viewed by 1599

Abstract

Maternal alcohol consumption is one of the strong predictive factors of alcohol use and consequent abuse; however, investigations of sex differences in response to prenatal alcohol exposure (PAE) are limited. Here we compared the effects of PAE throughout gestation on alcohol preference, state [...] Read more.

Maternal alcohol consumption is one of the strong predictive factors of alcohol use and consequent abuse; however, investigations of sex differences in response to prenatal alcohol exposure (PAE) are limited. Here we compared the effects of PAE throughout gestation on alcohol preference, state anxiety and mRNA expression of presynaptic proteins α-, β- and γ-synucleins in the brain of adult (PND60) male and female Wistar rats. Total RNA was isolated from the hippocampus, midbrain and hypothalamus and mRNA levels were assessed with quantitative RT-PCR. Compared with naïve males, naïve female rats consumed more alcohol in “free choice” paradigm (10% ethanol vs. water). At the same time, PAE produced significant increase in alcohol consumption and preference in males but not in females compared to male and female naïve groups, correspondingly. We found significantly lower α-synuclein mRNA levels in the hippocampus and midbrain of females compared to males and significant decrease in α-synuclein mRNA in these brain areas in PAE males, but not in females compared to the same sex controls. These findings indicate that the impact of PAE on transcriptional regulation of synucleins may be sex-dependent, and in males’ disruption in α-synuclein mRNA expression may contribute to increased vulnerability to alcohol-associated behavior. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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Review

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17 pages, 1623 KiB

Open AccessReview

The Role of α-Synuclein in the Regulation of Serotonin System: Physiological and Pathological Features

by Lluis Miquel-Rio, Unai Sarriés-Serrano, Rubén Pavia-Collado, J Javier Meana and Analia Bortolozzi

Biomedicines 2023, 11(2), 541; https://doi.org/10.3390/biomedicines11020541 - 13 Feb 2023

Cited by 7 | Viewed by 3043

Abstract

In patients affected by Parkinson’s disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is [...] Read more.

In patients affected by Parkinson’s disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein (α-Syn). Much of PD research has focused on the role of α-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of α-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of α-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to α-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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17 pages, 763 KiB

Open AccessReview

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

by Andrei Surguchov and Alexei Surguchev

Biomedicines 2022, 10(12), 3241; https://doi.org/10.3390/biomedicines10123241 - 13 Dec 2022

Cited by 19 | Viewed by 1944

Abstract

The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over [...] Read more.

The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over 35 years. Two reasons explain this unchanging attention: synuclein’s association with several severe human diseases and the lack of understanding of the functional roles under normal physiological conditions. We analyzed recent publications to look at the main trends and developments in synuclein research and discuss possible future directions. Traditional areas of peak research interest which still remain high among last year’s publications are comparative studies of structural features as well as functional research on of three members of the synuclein family. Another popular research topic in the area is a mechanism of α-synuclein accumulation, aggregation, and fibrillation. Exciting fast-growing area of recent research is α-synuclein and epigenetics. We do not present here a broad and comprehensive review of all directions of studies but summarize only the most significant recent findings relevant to these topics and outline potential future directions. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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27 pages, 745 KiB

Open AccessReview

Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study

by Katrina Albert, Sara Kälvälä, Vili Hakosalo, Valtteri Syvänen, Patryk Krupa, Jonna Niskanen, Sanni Peltonen, Tuuli-Maria Sonninen and Šárka Lehtonen

Biomedicines 2022, 10(10), 2649; https://doi.org/10.3390/biomedicines10102649 - 20 Oct 2022

Cited by 4 | Viewed by 4220

Abstract

Alpha-synuclein’s role in diseases termed “synucleinopathies”, including Parkinson’s disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful [...] Read more.

Alpha-synuclein’s role in diseases termed “synucleinopathies”, including Parkinson’s disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful tools that researchers have at their disposal to understand protein function. Advantages include good control over experimental conditions, the possibility for high throughput, and fewer ethical issues when compared to animal models or the attainment of human samples. On the flip side, their major disadvantages are their questionable relevance and lack of a “whole-brain” environment when it comes to modeling human diseases, such as is the case of neurodegenerative disorders. Although now, with the advent of pluripotent stem cells and the ability to create minibrains in a dish, this is changing. With this review, we aim to wade through the recent alpha-synuclein literature to discuss how different cell culture setups (immortalized cell lines, primary neurons, human induced pluripotent stem cells (hiPSCs), blood–brain barrier models, and brain organoids) can help us understand aggregation pathology in Parkinson’s and other synucleinopathies. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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15 pages, 747 KiB

Open AccessReview

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

by Valeria V. Goloborshcheva, Valerian G. Kucheryanu, Natalia A. Voronina, Ekaterina V. Teterina, Aleksey A. Ustyugov and Sergei G. Morozov

Biomedicines 2022, 10(9), 2278; https://doi.org/10.3390/biomedicines10092278 - 14 Sep 2022

Cited by 4 | Viewed by 3385

Abstract

Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked [...] Read more.

Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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12 pages, 1080 KiB

Open AccessCommentary

Surgical Management of Synucleinopathies

by Sai Sriram, Kevin Root, Kevin Chacko, Aashay Patel and Brandon Lucke-Wold

Biomedicines 2022, 10(10), 2657; https://doi.org/10.3390/biomedicines10102657 - 21 Oct 2022

Cited by 4 | Viewed by 1614

Abstract

Synucleinopathies represent a diverse set of pathologies with significant morbidity and mortality. In this review, we highlight the surgical management of three synucleinopathies: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). After examining underlying molecular mechanisms and the [...] Read more.

Synucleinopathies represent a diverse set of pathologies with significant morbidity and mortality. In this review, we highlight the surgical management of three synucleinopathies: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). After examining underlying molecular mechanisms and the medical management of these diseases, we explore the role of deep brain stimulation (DBS) in the treatment of synuclein pathophysiology. Further, we examine the utility of focused ultrasound (FUS) in the treatment of synucleinopathies such as PD, including its role in blood–brain barrier (BBB) opening for the delivery of novel drug therapeutics and gene therapy vectors. We also discuss other recent advances in the surgical management of MSA and DLB. Together, we give a diverse overview of current techniques in the neurosurgical management of these pathologies. Full article

(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)

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