Molecular Insights into Neurodegenerative Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 14626

Special Issue Editor


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Guest Editor
Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
Interests: neurodegenerative diseases; Alzheimer’s disease; dementia; cell biology; molecular biology; ageing; therapeutics
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Special Issue Information

Dear Colleagues,

Neurodegenerative disorders/diseases is an umbrella term that refers to diseases of the nervous system. The main components of the nervous system are neurons and neuroglial cells. The functioning of these cells is paramount to the existence of life. Stress, toxins, lifestyle, environmental factors and genetics are a few of the numerous factors that can influence the cellular and molecular functioning of neurons and neuroglia. Recent advances in the fields of molecular biology, genomics and proteomics have provided significant insight into the functioning of the nervous system. Advances in technologies that garner information from the fields of bioinformatics and next generation and whole genome sequencing have added invaluable support in identifying ‘culprit’ genes and proteins. Using this information, scientists and clinicians have ventured into areas previously deemed ‘fiction’.

In this Special Issue, we aim to draw together research from experts in the field that highlight discoveries of novel molecular underpinnings of neurodegenerative diseases. These discoveries could lead to the identification of therapeutic agents and strategies and identify future directions that will lead to discoveries and therapies for neurological disorders. 

Dr. Damian Holsinger
Guest Editor

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Keywords

  • Alzheimer’s disease
  • Parkinson’s disease
  • Amyotrophic Lateral Sclerosis
  • Huntington’s disease
  • multiple system atrophy
  • Prion diseases
  • Synucleinopathies
  • Spinocerebellar ataxia
  • Frontotemporal Dementia

Published Papers (8 papers)

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Research

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14 pages, 1645 KiB  
Article
Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy
by Paola Ruffo, Francesca De Amicis, Vincenzo La Bella and Francesca Luisa Conforti
Cells 2024, 13(8), 677; https://doi.org/10.3390/cells13080677 - 14 Apr 2024
Viewed by 262
Abstract
The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences [...] Read more.
The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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17 pages, 4251 KiB  
Article
Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport
by Svenja König, Nadine Schmidt, Karin Bechberger, Sarah Morris, Mercedes Priego, Hannah Zaky, Yuyu Song, Jan Pielage, Silke Brunholz, Scott T. Brady, Stefan Kins and Gerardo Morfini
Cells 2023, 12(19), 2403; https://doi.org/10.3390/cells12192403 - 04 Oct 2023
Viewed by 1655
Abstract
The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of [...] Read more.
The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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11 pages, 1661 KiB  
Article
Basal Ganglia Compensatory White Matter Changes on DTI in Alzheimer’s Disease
by Zdeněk Wurst, Barbora Birčák Kuchtová, Jan Křemen, Anastasiya Lahutsina, Ibrahim Ibrahim, Jaroslav Tintěra, Aleš Bartoš, Marek Brabec, Tanya Rai, Petr Zach, Vladimír Musil, Nicoletta Olympiou and Jana Mrzílková
Cells 2023, 12(9), 1220; https://doi.org/10.3390/cells12091220 - 23 Apr 2023
Cited by 2 | Viewed by 1704
Abstract
The volume reduction of the gray matter structures in patients with Alzheimer’s disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes [...] Read more.
The volume reduction of the gray matter structures in patients with Alzheimer’s disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes in the motor basal ganglia in Alzheimer’s disease patients compared to healthy controls using diffusion tensor imaging. The amounts of tracts, tract length, tract volume, quantitative anisotropy, and general fractional anisotropy were measured in ten patients with Alzheimer’s disease and ten healthy controls. A significant decrease in the number of tracts and general fractional anisotropy was found in patients with Alzheimer’s disease compared to controls in the right caudate nucleus, while an increase was found in the left and the right putamen. Further, a significant decrease in the structural volume of the left and the right putamen was observed. An increase in the white matter diffusion tensor imaging parameters in patients with Alzheimer’s disease was observed only in the putamen bilaterally. The right caudate showed a decrease in both the diffusion tensor imaging parameters and the volume in Alzheimer’s disease patients. The right pallidum showed an increase in the diffusion tensor imaging parameters but a decrease in volume in Alzheimer’s disease patients. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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15 pages, 3128 KiB  
Article
Fecal Microbiota Transplantation Reduces Pathology and Improves Cognition in a Mouse Model of Alzheimer’s Disease
by Shalini Elangovan, Thomas J. Borody and R. M. Damian Holsinger
Cells 2023, 12(1), 119; https://doi.org/10.3390/cells12010119 - 28 Dec 2022
Cited by 12 | Viewed by 3319
Abstract
Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota [...] Read more.
Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota transplantation (FMT) is a widely accepted and safely used treatment for recurrent Clostridium difficile infection and other metabolic diseases such as diabetes mellitus. FMT has also been demonstrated to be a possible AD therapeutic. We examined the potential of FMT for the treatment of AD in a robust, mouse model of the disease and report that a brief, 7-day treatment regimen demonstrated ‘plaque-busting’ and behavior-modifying effects in treated 5xFAD mice. Importantly, we show that donor age plays an important role in the efficacy of the treatment and these findings warrant further investigation in human trials. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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Review

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16 pages, 792 KiB  
Review
Proximity-Induced Pharmacology for Amyloid-Related Diseases
by Andrea Bertran-Mostazo, Gabrielė Putriūtė, Irene Álvarez-Berbel, Maria Antònia Busquets, Carles Galdeano, Alba Espargaró and Raimon Sabate
Cells 2024, 13(5), 449; https://doi.org/10.3390/cells13050449 - 04 Mar 2024
Viewed by 908
Abstract
Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic [...] Read more.
Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer’s disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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25 pages, 2876 KiB  
Review
Pharmacotherapy Evolution in Alzheimer’s Disease: Current Framework and Relevant Directions
by Denisa Claudia Miculas, Paul Andrei Negru, Simona Gabriela Bungau, Tapan Behl, Syed Shams ul Hassan and Delia Mirela Tit
Cells 2023, 12(1), 131; https://doi.org/10.3390/cells12010131 - 28 Dec 2022
Cited by 18 | Viewed by 3549
Abstract
Alzheimer’s disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of [...] Read more.
Alzheimer’s disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of the disease. Since the last several decades, there has been a great need for the development of a treatment that might cure the underlying causes of AD and thereby slow its progression in vulnerable individuals. That is why phase I, II, and III studies that act on several fronts, such as cognitive improvement, symptom reduction, and enhancing the basic biology of AD, are imperative to stop the disease. This review discusses current treatment strategies, summarizing the clinical features and pharmacological properties, along with molecular docking analyses of the existing medications. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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Other

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16 pages, 590 KiB  
Opinion
Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism
by Balázs Sonkodi
Cells 2024, 13(6), 492; https://doi.org/10.3390/cells13060492 - 12 Mar 2024
Viewed by 947
Abstract
Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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16 pages, 1883 KiB  
Perspective
Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP
by Judit Oláh, Vic Norris, Attila Lehotzky and Judit Ovádi
Cells 2024, 13(4), 338; https://doi.org/10.3390/cells13040338 - 14 Feb 2024
Viewed by 926
Abstract
Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin [...] Read more.
Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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