Editorial

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Open AccessEditorial

Neurodegenerative Diseases: Molecular Mechanisms and Therapies

by Zhi Dong Zhou and Alexandre Hiroaki Kihara

Int. J. Mol. Sci. 2023, 24(18), 13721; https://doi.org/10.3390/ijms241813721 - 06 Sep 2023

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Neurodegenerative diseases are characterized by the progressive degeneration or death of neurons in the central or peripheral nervous system [...] Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

Research

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15 pages, 3076 KiB

Open AccessCommunication

Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer’s Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil

by Richard Killick, Christina Elliott, Elena Ribe, Martin Broadstock, Clive Ballard, Dag Aarsland and Gareth Williams

Int. J. Mol. Sci. 2023, 24(13), 11219; https://doi.org/10.3390/ijms241311219 - 07 Jul 2023

Cited by 2 | Viewed by 1586

Abstract

The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic [...] Read more.

The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer’s disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer’s and Parkinson’s diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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21 pages, 3542 KiB

Open AccessArticle

Parkin Precipitates on Mitochondria via Aggregation and Autoubiquitination

by Mustafa T. Ardah, Nada Radwan, Engila Khan, Tohru Kitada and M Emdadul Haque

Int. J. Mol. Sci. 2023, 24(10), 9027; https://doi.org/10.3390/ijms24109027 - 19 May 2023

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Abstract

The loss of the E3 ligase Parkin, in a familial form of Parkinson’s disease, is thought to cause the failure of both the polyubiquitination of abnormal mitochondria and the consequent induction of mitophagy, resulting in abnormal mitochondrial accumulation. However, this has not been [...] Read more.

The loss of the E3 ligase Parkin, in a familial form of Parkinson’s disease, is thought to cause the failure of both the polyubiquitination of abnormal mitochondria and the consequent induction of mitophagy, resulting in abnormal mitochondrial accumulation. However, this has not been confirmed in patient autopsy cases or animal models. More recently, the function of Parkin as a redox molecule that directly scavenges hydrogen peroxide has attracted much attention. To determine the role of Parkin as a redox molecule in the mitochondria, we overexpressed various combinations of Parkin, along with its substrates FAF1, PINK1, and ubiquitin in cell culture systems. Here, we observed that the E3 Parkin monomer was surprisingly not recruited to abnormal mitochondria but self-aggregated with or without self-ubiquitination into the inner and outer membranes, becoming insoluble. Parkin overexpression alone generated aggregates without self-ubiquitination, but it activated autophagy. These results suggest that for damaged mitochondria, the polyubiquitination of Parkin substrates on the mitochondria is not indispensable for mitophagy. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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11 pages, 4675 KiB

Open AccessArticle

Effect of Electric Field on α-Synuclein Fibrils: Revealed by Molecular Dynamics Simulations

by Jamoliddin Razzokov, Sunnatullo Fazliev, Mukhriddin Makhkamov, Parthiban Marimuthu, Artyom Baev and Erkin Kurganov

Int. J. Mol. Sci. 2023, 24(7), 6312; https://doi.org/10.3390/ijms24076312 - 28 Mar 2023

Cited by 4 | Viewed by 2033

Abstract

The self-association of amylogenic proteins to the fibril form is considered a pivotal factor in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). PD causes unintended or uncontrollable movements in its common symptoms. α-synuclein is the major cause of PD development and [...] Read more.

The self-association of amylogenic proteins to the fibril form is considered a pivotal factor in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). PD causes unintended or uncontrollable movements in its common symptoms. α-synuclein is the major cause of PD development and thus has been the main target of numerous studies to suppress and sequester its expression or effectively degrade it. Nonetheless, to date, there are no efficient and proven ways to prevent pathological protein aggregation. Recent investigations proposed applying an external electric field to interrupt the fibrils. This method is a non-invasive approach that has a certain benefit over others. We performed molecular dynamics (MD) simulations by applying an electric field on highly toxic fibrils of α-synuclein to gain a molecular-level insight into fibril disruption mechanisms. The results revealed that the applied external electric field induces substantial changes in the conformation of the α-synuclein fibrils. Furthermore, we show the threshold value for electric field strength required to completely disrupt the α-synuclein fibrils by opening the hydrophobic core of the fibril. Thus, our findings might serve as a valuable foundation to better understand molecular-level mechanisms of the α-synuclein fibrils disaggregation process under an applied external electric field. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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19 pages, 3624 KiB

Open AccessArticle

Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

by Nadia Papini, Roberta Todisco, Paola Giussani, Michele Dei Cas, Rita Paroni, Chiara Giallanza and Cristina Tringali

Int. J. Mol. Sci. 2023, 24(6), 5984; https://doi.org/10.3390/ijms24065984 - 22 Mar 2023

Cited by 7 | Viewed by 1504

Abstract

Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming [...] Read more.

Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming a promising target for supportive therapies. Autophagy alterations were recently identified also in Krabbe disease. Krabbe disease is characterized by extensive demyelination and dysmyelination and it is due to the genetic loss of function of the lysosomal enzyme galactocerebrosidase (GALC). This enzyme leads to the accumulation of galactosylceramide, psychosine, and secondary substrates such as lactosylceramide. In this paper, we induced autophagy through starvation and examined the cellular response occurring in fibroblasts isolated from patients. We demonstrated that the inhibitory AKT-mediated phosphorylation of beclin-1 and the BCL2-beclin-1 complex concur to reduce autophagosomes formation in response to starvation. These events were not dependent on the accumulation of psychosine, which was previously identified as a possible player in autophagic impairment in Krabbe disease. We believe that these data could better elucidate the capability of response to autophagic stimuli in Krabbe disease, in order to identify possible molecules able to stimulate the process. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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28 pages, 15567 KiB

Open AccessArticle

Overexpression of a Novel Noxo1 Mutant Increases Ros Production and Noxo1 Relocalisation

by Fatima-Zahra Benssouina, Fabrice Parat, Claude Villard, Ludovic Leloup, Françoise Garrouste, Jean-marc Sabatier, Lotfi Ferhat and Hervé Kovacic

Int. J. Mol. Sci. 2023, 24(5), 4663; https://doi.org/10.3390/ijms24054663 - 28 Feb 2023

Cited by 1 | Viewed by 1431

Abstract

Noxo1, the organizing element of the Nox1-dependent NADPH oxidase complex responsible for producing reactive oxygen species, has been described to be degraded by the proteasome. We mutated a D-box in Noxo1 to express a protein with limited degradation and capable of maintaining Nox1 [...] Read more.

Noxo1, the organizing element of the Nox1-dependent NADPH oxidase complex responsible for producing reactive oxygen species, has been described to be degraded by the proteasome. We mutated a D-box in Noxo1 to express a protein with limited degradation and capable of maintaining Nox1 activation. Wild-type (wt) and mutated Noxo1 (mut1) proteins were expressed in different cell lines to characterize their phenotype, functionality, and regulation. Mut1 increases ROS production through Nox1 activity affects mitochondrial organization and increases cytotoxicity in colorectal cancer cell lines. Unexpectedly the increased activity of Noxo1 is not related to a blockade of its proteasomal degradation since we were unable in our conditions to see any proteasomal degradation either for wt or mut1 Noxo1. Instead, D-box mutation mut1 leads to an increased translocation from the membrane soluble fraction to a cytoskeletal insoluble fraction compared to wt Noxo1. This mut1 localization is associated in cells with a filamentous phenotype of Noxo1, which is not observed with wt Noxo1. We found that mut1 Noxo1 associates with intermediate filaments such as keratin 18 and vimentin. In addition, Noxo1 D-Box mutation increases Nox1-dependent NADPH oxidase activity. Altogether, Nox1 D-box does not seem to be involved in Noxo1 degradation but rather related to the maintenance of the Noxo1 membrane/cytoskeleton balance. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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14 pages, 3387 KiB

Open AccessArticle

Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease

by Monica Cattaneo, Anna Maciag, Maria Serena Milella, Elena Ciaglia, Antonino Bruno and Annibale Alessandro Puca

Int. J. Mol. Sci. 2022, 23(23), 15313; https://doi.org/10.3390/ijms232315313 - 05 Dec 2022

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Abstract

Huntington’s disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived [...] Read more.

Huntington’s disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdh^Q111/Q111), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the longevity-associated variant (LAV) of BPIFB4 prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdh^Q111/Q111 cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin–proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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14 pages, 3480 KiB

Open AccessArticle

Oligomerization of Human Cystatin C—An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies

by Daria Wojciechowska, Michał Taube, Karolina Rucińska, Joanna Maksim and Maciej Kozak

Int. J. Mol. Sci. 2022, 23(21), 13441; https://doi.org/10.3390/ijms232113441 - 03 Nov 2022

Cited by 2 | Viewed by 1318

Abstract

Human cystatin C (HCC), an amyloidogenic protein, forms dimers and higher oligomers (trimers, tetramers and donut like large oligomers) via a domain-swapping mechanism. The aim of this study was the characterization of the HCC oligomeric states observed within the pH range from 2.2 [...] Read more.

Human cystatin C (HCC), an amyloidogenic protein, forms dimers and higher oligomers (trimers, tetramers and donut like large oligomers) via a domain-swapping mechanism. The aim of this study was the characterization of the HCC oligomeric states observed within the pH range from 2.2 to 10.0 and also in conditions promoting oligomerization. The HCC oligomeric forms obtained in different conditions were characterized using size exclusion chromatography, dynamic light scattering and small-angle X-ray scattering. The marked ability of HCC to form tetramers at low pH (2.3 or 3.0) and dimers at pH 4.0–5.0 was observed. HCC remains monomeric at pH levels above 6.0. Based on the SAXS data, the structure of the HCC tetramer was proposed. Changes in the environment (from acid to neutral) induced a breakdown of the HCC tetramers to dimers. The tetrameric forms of human cystatin C are formed by the association of the dimers without a domain-swapping mechanism. These observations were confirmed by their dissociation to dimers at pH 7.4. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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Review

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Open AccessReview

Advancements in the Application of Nanomedicine in Alzheimer’s Disease: A Therapeutic Perspective

by Nidhi Puranik, Dhananjay Yadav and Minseok Song

Int. J. Mol. Sci. 2023, 24(18), 14044; https://doi.org/10.3390/ijms241814044 - 13 Sep 2023

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood–brain and blood–cerebrospinal fluid barriers are two [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood–brain and blood–cerebrospinal fluid barriers are two barriers that protect the central nervous system, their presence has severely restricted the efficacy of many treatments that have been studied for AD diagnosis and/or therapy. The use of nanoparticles for the diagnosis and treatment of AD is the focus of an established and rapidly developing field of nanomedicine. Recent developments in nanomedicine have made it possible to effectively transport drugs to the brain. However, numerous obstacles remain to the successful use of nanomedicines in clinical settings for AD treatment. Furthermore, given the rapid advancement in nanomedicine therapeutics, better outcomes for patients with AD can be anticipated. This article provides an overview of recent developments in nanomedicine using different types of nanoparticles for the management and treatment of AD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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23 pages, 2967 KiB

Open AccessReview

α-Synuclein Strains and Their Relevance to Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy Bodies

by Noah J. Graves, Yann Gambin and Emma Sierecki

Int. J. Mol. Sci. 2023, 24(15), 12134; https://doi.org/10.3390/ijms241512134 - 28 Jul 2023

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Abstract

Like many neurodegenerative diseases, Parkinson’s disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn [...] Read more.

Like many neurodegenerative diseases, Parkinson’s disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn pathological aggregation is also detected in atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well as neurodegeneration with brain iron accumulation, some cases of traumatic brain injuries, and variants of Alzheimer’s disease. Collectively, these (and other) disorders are referred to as synucleinopathies, highlighting the relation between disease type and protein misfolding/aggregation. Despite these pathological relationships, however, synucleinopathies cover a wide range of pathologies, present with a multiplicity of symptoms, and arise from dysfunctions in different neuroanatomical regions and cell populations. Strikingly, αSyn deposition occurs in different types of cells, with oligodendrocytes being mainly affected in MSA, while aggregates are found in neurons in PD. If multiple factors contribute to the development of a pathology, especially in the cases of slow-developing neurodegenerative disorders, the common presence of αSyn aggregation, as both a marker and potential driver of disease, is puzzling. In this review, we will focus on comparing PD, DLB, and MSA, from symptomatology to molecular description, highlighting the role and contribution of αSyn aggregates in each disorder. We will particularly present recent evidence for the involvement of conformational strains of αSyn aggregates and discuss the reciprocal relationship between αSyn strains and the cellular milieu. Moreover, we will highlight the need for effective methodologies for the strainotyping of aggregates to ameliorate diagnosing capabilities and therapeutic treatments. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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19 pages, 2296 KiB

Open AccessReview

Role of Exosomes in the Pathogenesis and Theranostic of Alzheimer’s Disease and Parkinson’s Disease

by Aojie He, Meiling Wang, Xiaowan Li, Hong Chen, Kahleong Lim, Li Lu and Chengwu Zhang

Int. J. Mol. Sci. 2023, 24(13), 11054; https://doi.org/10.3390/ijms241311054 - 04 Jul 2023

Cited by 1 | Viewed by 2519

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDDs) threatening the lives of millions of people worldwide, including especially elderly people. Currently, due to the lack of a timely diagnosis and proper intervention strategy, AD and PD largely [...] Read more.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDDs) threatening the lives of millions of people worldwide, including especially elderly people. Currently, due to the lack of a timely diagnosis and proper intervention strategy, AD and PD largely remain incurable. Innovative diagnosis and therapy are highly desired. Exosomes are small vesicles that are present in various bodily fluids, which contain proteins, nucleic acids, and active biomolecules, and which play a crucial role especially in intercellular communication. In recent years, the role of exosomes in the pathogenesis, early diagnosis, and treatment of diseases has attracted ascending attention. However, the exact role of exosomes in the pathogenesis and theragnostic of AD and PD has not been fully illustrated. In the present review, we first introduce the biogenesis, components, uptake, and function of exosomes. Then we elaborate on the involvement of exosomes in the pathogenesis of AD and PD. Moreover, the application of exosomes in the diagnosis and therapeutics of AD and PD is also summarized and discussed. Additionally, exosomes serving as drug carriers to deliver medications to the central nervous system are specifically addressed. The potential role of exosomes in AD and PD is explored, discussing their applications in diagnosis and treatment, as well as their current limitations. Given the limitation in the application of exosomes, we also propose future perspectives for better utilizing exosomes in NDDs. Hopefully, it would pave ways for expanding the biological applications of exosomes in fundamental research as well as theranostics of NDDs. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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28 pages, 2743 KiB

Open AccessReview

Experimental Models of In Vitro Blood–Brain Barrier for CNS Drug Delivery: An Evolutionary Perspective

by Bivek Chaulagain, Avinash Gothwal, Richard Nii Lante Lamptey, Riddhi Trivedi, Arun Kumar Mahanta, Buddhadev Layek and Jagdish Singh

Int. J. Mol. Sci. 2023, 24(3), 2710; https://doi.org/10.3390/ijms24032710 - 31 Jan 2023

Cited by 9 | Viewed by 3066

Abstract

Central nervous system (CNS) disorders represent one of the leading causes of global health burden. Nonetheless, new therapies approved against these disorders are among the lowest compared to their counterparts. The absence of reliable and efficient in vitro blood–brain barrier (BBB) models resembling [...] Read more.

Central nervous system (CNS) disorders represent one of the leading causes of global health burden. Nonetheless, new therapies approved against these disorders are among the lowest compared to their counterparts. The absence of reliable and efficient in vitro blood–brain barrier (BBB) models resembling in vivo barrier properties stands out as a significant roadblock in developing successful therapy for CNS disorders. Therefore, advancement in the creation of robust and sensitive in vitro BBB models for drug screening might allow us to expedite neurological drug development. This review discusses the major in vitro BBB models developed as of now for exploring the barrier properties of the cerebral vasculature. Our main focus is describing existing in vitro models, including the 2D transwell models covering both single-layer and co-culture models, 3D organoid models, and microfluidic models with their construction, permeability measurement, applications, and limitations. Although microfluidic models are better at recapitulating the in vivo properties of BBB than other models, significant gaps still exist for their use in predicting the performance of neurotherapeutics. However, this comprehensive account of in vitro BBB models can be useful for researchers to create improved models in the future. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)

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