Neuromuscular and Neurodegenerative Diseases: Towards Personalized Medicine, Therapeutics and Improved Mechanistic Understanding

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 40457

Special Issue Editors


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Guest Editor
Faculty of Life and Health Sciences, School of Mecidine, Centre of Personalised Medicine, Ulster University, Coleraine, UK
Interests: neuromuscular disorders; motor neuron diseases; extracellular vesicles; mitochondrial biogenesis; muscle ageing; myoblasts; DNA methylation; Duchenne-Becker; amyotrophic lateral sclerosis (ALS); spino-bulbar muscular atrophy (SBMA); spinal muscular atrophy (SMA)
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Laboratoire d’Imagerie Biomédicale, Sorbonne Universités, CNRS, INSERM, Paris, France
Interests: motor neurone diseases; SMA type IV; clinical trial; neurons; diagnostic imaging; muscular atrophy; biomarkers; motor skills disorders; neurodegeneration

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Guest Editor
NIHR Biomedical Research Centre, Great Ormond Street Institute of Child Health, Great Ormond Street Hospital NHS Trust, University College London, London WC1N 1EH, UK
Interests: neuromuscular disorders; therapeutics; adeno-associated-virus (AAV); muscle cell immortalization; iPS; animal model; facioscapulohumeral muscular dystrophy (FSHD); myotonic dystrophy; Duchenne-Becker- and limb girdle muscular dystrophy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue focuses on neuromuscular and neurodegenerative diseases in childhood and adult life (including muscular dystrophies, spinal muscular atrophies, myotonic syndromes, metabolic myopathies, myasthenia gravis, hereditary myopathies, metabolic and inflammatory myopathies, motor neuron diseases, dementia, Parkinsonism, Huntington disease etc).

Advancing research for neuromuscular and neurodegenerative diseases requires a coordinated effort between clinicians, scientists, patients and their families, and other stakeholders. This collaboration drives the collection of samples and the direction of clinical investigation, and combined with recent progress in terms of genetic and genomic analysis has enabled the research community to make real gains towards improvements in patient care, such as the identification of specific genetic factors that have a key role in pathogenesis. Indeed, genetic and genomic analyses not only allow the identification of monogenic and polygenic causes of heritable diseases, but can also identify modifiers that can influence the course and severity of a given disease.

The identification of different groups and subgroups of patients affected by a specific disease pushes the scientific community to move toward personalised/stratified therapeutic strategies. The recent development of multidisciplinary approaches such as multi-omics analysis, electrophysiological and neuroimaging measures, as well as cellular and animal models is having an important impact on medical advances for these types of disease.

Deciphering the cascade of mechanisms being affected in each subgroup improves our understanding of a given disease and helps us to identify biomarkers and therapeutic strategies.

This Special Issue is dedicated to recent research progress in neuromuscular and neurodegenerative diseases, with a focus on:

  • Biomarkers: diagnostic, prognostic, patient stratification, wet biomarkers (in body fluids), dry biomarkers (imaging, neuroimaging, electrophysiology);
  • Clinical indicators;
  • Mechanisms explaining or contributing to irreversible cell loss;
  • Therapeutic strategies.

Up-to-date original research papers, communications and reviews will be considered

We look forward to your contributions to this Special Issue.

Dr. Stephanie Duguez
Prof. Dr. Pierre Francois Pradat
Prof. Dr. Julie Dumonceaux
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuromuscular diseases
  • neurodegenerative diseases
  • functional genomics
  • gene therapies
  • molecular biology
  • patient stratification
  • therapeutic strategies
  • biomarkers
  • electrophysiological measures
  • neuroimaging

Published Papers (13 papers)

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Research

Jump to: Review

20 pages, 3517 KiB  
Article
Molecular and Phenotypic Changes in FLExDUX4 Mice
by Kelly Murphy, Aiping Zhang, Adam J. Bittel and Yi-Wen Chen
J. Pers. Med. 2023, 13(7), 1040; https://doi.org/10.3390/jpm13071040 - 25 Jun 2023
Viewed by 1241
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. The FLExDUX4 mouse model carries an inverted human DUX4 transgene which has leaky DUX4 transgene expression at a very low level. No overt muscle [...] Read more.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. The FLExDUX4 mouse model carries an inverted human DUX4 transgene which has leaky DUX4 transgene expression at a very low level. No overt muscle pathology was reported before 16 weeks. The purpose of this study is to track and characterize the FLExDUX4 phenotypes for a longer period, up to one year old. In addition, transcriptomic changes in the muscles of 2-month-old mice were investigated using RNA-seq. The results showed that male FLExDUX4 mice developed more severe phenotypes and at a younger age in comparison to the female mice. These include lower body and muscle weight, and muscle weakness measured by grip strength measurements. Muscle pathological changes were observed at older ages, including fibrosis, decreased size of type IIa and IIx myofibers, and the development of aggregates containing TDP-43 in type IIb myofibers. Muscle transcriptomic data identified early molecular changes in biological pathways regulating circadian rhythm and adipogenesis. The study suggests a slow progressive change in molecular and muscle phenotypes in response to the low level of DUX4 expression in the FLExDUX4 mice. Full article
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13 pages, 847 KiB  
Article
Possible Incidental Parkinson’s Disease following Asthma: A Nested Case–Control Study in Korea
by Mi Jung Kwon, Joo-Hee Kim, Ho Suk Kang, Hyun Lim, Min-Jeong Kim, Nan Young Kim, Se Hoon Kim, Hyo Geun Choi and Eun Soo Kim
J. Pers. Med. 2023, 13(5), 718; https://doi.org/10.3390/jpm13050718 - 24 Apr 2023
Cited by 2 | Viewed by 1337
Abstract
A connection between asthma and the occurrence of Parkinson’s disease (PD) has been suggested, but the findings have been contentious and require verification. In this nested case–control study using data from the Korean National Health Insurance Service—Health Screening Cohort (2002–2019), which comprised 9029 [...] Read more.
A connection between asthma and the occurrence of Parkinson’s disease (PD) has been suggested, but the findings have been contentious and require verification. In this nested case–control study using data from the Korean National Health Insurance Service—Health Screening Cohort (2002–2019), which comprised 9029 participants with PD and 36,116 matched controls, we explored the relationship between asthma and incident PD. An overlap-weighted logistic regression model was used to measure the probability of asthma and PD. After adjusting for various covariates, we found that asthma was related to a 1.11-fold greater probability of PD (95% confidence interval: 1.06–1.16). A subgroup analysis showed that this effect was independent of age, sex, residential area, or alcohol consumption, and that it was still noticeable even among patients with a high income; those with a normal weight or obesity; those who were non-smokers or current smokers; and those with no history of chronic obstructive pulmonary disease, hypertension, hyperglycemia, hyperlipidemia, or anemia. Thus, these findings may indicate that asthma may slightly augment the likelihood of PD in the Korean adult population regardless of demographic or lifestyle factors, making it difficult to predict PD in asthma patients. Full article
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11 pages, 2798 KiB  
Article
Impaired Interhemispheric Synchrony in Parkinson’s Disease with Fatigue
by Yong-Sheng Yuan, Min Ji, Cai-Ting Gan, Hui-Min Sun, Li-Na Wang and Ke-Zhong Zhang
J. Pers. Med. 2022, 12(6), 884; https://doi.org/10.3390/jpm12060884 - 27 May 2022
Cited by 2 | Viewed by 1584
Abstract
The characteristics of interhemispheric resting-state functional connectivity (FC) in Parkinson’s disease (PD) with fatigue remain unclear; therefore, we aimed to explore the changes in interhemispheric FC in PD patients with fatigue. Sixteen PD patients with fatigue (PDF), 16 PD patients without fatigue (PDNF) [...] Read more.
The characteristics of interhemispheric resting-state functional connectivity (FC) in Parkinson’s disease (PD) with fatigue remain unclear; therefore, we aimed to explore the changes in interhemispheric FC in PD patients with fatigue. Sixteen PD patients with fatigue (PDF), 16 PD patients without fatigue (PDNF) and 15 matched healthy controls (HCs) were enrolled in the retrospective cross-sectional study. We used voxel-mirrored homotopic connectivity (VMHC) to analyze the resting-state functional magnetic resonance imaging (fMRI) data of these subjects. Compared to PDNF, PDF patients had decreased VMHC values in the supramarginal gyri (SMG). Furthermore, the mean VMHC values of the SMG were negatively correlated with the mean fatigue severity scale (FSS/9) scores (r = −0.754, p = 0.001). Compared to HCs, PDF patients had decreased VMHC in the SMG and in the opercular parts of the inferior frontal gyri (IFG operc). The VMHC values in the IFG operc and middle frontal gyri (MFG) were notably decreased in PDNF patients compared with HCs. Our findings suggest that the reduced VMHC values within the bilateral SMG may be the unique imaging features of fatigue in PD, and may illuminate the neural mechanisms of fatigue in PD. Full article
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7 pages, 253 KiB  
Article
Constipation Symptoms in Multiple System Atrophy Using Rome Criteria and Their Impact on Personalized Medicine
by Takayasu Mishima, Shinsuke Fujioka, Miki Kawazoe, Kotoe Inoue, Hisatomi Arima and Yoshio Tsuboi
J. Pers. Med. 2022, 12(5), 838; https://doi.org/10.3390/jpm12050838 - 20 May 2022
Cited by 6 | Viewed by 1637
Abstract
Constipation is one of the most common non-motor symptoms in multiple system atrophy (MSA); however, it has not been evaluated according to the standard diagnostic criteria for constipation in patients with MSA. We evaluated the characteristics of constipation in patients with MSA by [...] Read more.
Constipation is one of the most common non-motor symptoms in multiple system atrophy (MSA); however, it has not been evaluated according to the standard diagnostic criteria for constipation in patients with MSA. We evaluated the characteristics of constipation in patients with MSA by using Rome criteria (Rome III), which has been validated and the widely used for gastrointestinal disorders. Fifty-one patients with MSA (29 female) were enrolled in the study. Based on the Rome III criteria, constipation was diagnosed in 29 patients (56.9%); irritable bowel syndrome was not detected. Thirty-seven patients (72.5%) were aware of their constipation. The most common constipation symptom was the sensation of anorectal obstruction (68.6%). Patients’ self-awareness of constipation was most strongly correlated to the sensation of incomplete evacuation (odds ratio: 7.377, 95% confidence interval: 1.402–38.817). The number of constipation-related symptoms was correlated with the total levodopa equivalent dose (p < 0.05). Rome criteria, which can detect various constipation symptoms, are useful for evaluating constipation in MSA, and these findings may greatly impact personalized medicine. Full article
17 pages, 10276 KiB  
Article
Traceable Features of Static Plantar Pressure Characteristics and Foot Postures in College Students with Hemiplegic Cerebral Palsy
by Tong-Hsien Chow
J. Pers. Med. 2022, 12(3), 394; https://doi.org/10.3390/jpm12030394 - 04 Mar 2022
Cited by 1 | Viewed by 3203
Abstract
Patients with cerebral palsy (CP) are characterized by disturbances of mobility with postural and foot deformities. Subsequent development of CP may lead to changes in plantar loading. This study examined the characteristics of foot types and relative loads associated with centers of gravity [...] Read more.
Patients with cerebral palsy (CP) are characterized by disturbances of mobility with postural and foot deformities. Subsequent development of CP may lead to changes in plantar loading. This study examined the characteristics of foot types and relative loads associated with centers of gravity and foot posture in college students with left and right hemiplegic CP, as well as these differences between unaffected and hemiplegic limbs. A cross-sectional study of 45 hemiplegic college students with mild CP and 62 healthy students was conducted. Static plantar pressure was measured with a JC Mat. CP students exhibited low arches, and their plantar pressure distributions (PPDs) were mainly exerted on the left forefoot, as well as on the right forefoot and rearfoot. The weight shifted to the unaffected foot with dual plantar loading regions (forefoot and rearfoot), rather than the hemiplegic foot with a single region (forefoot). PPDs commonly increased at the medial metatarsals of both feet, and hemiplegic CP students presented the increased PPDs on the medial aspect of the hemiplegic foot accompanied by a rearfoot valgus posture pattern. The findings revealed a traceable feature to a possible connection among the pronated low arches, mild centers of gravity, metatarsal syndrome and rearfoot valgus of the hemiplegic limbs in CP patients. Full article
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Review

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13 pages, 591 KiB  
Review
Genetic Approaches for the Treatment of Giant Axonal Neuropathy
by Satomi Shirakaki, Rohini Roy Roshmi and Toshifumi Yokota
J. Pers. Med. 2023, 13(1), 91; https://doi.org/10.3390/jpm13010091 - 30 Dec 2022
Viewed by 2106
Abstract
Giant axonal neuropathy (GAN) is a pediatric, hereditary, neurodegenerative disorder that affects both the central and peripheral nervous systems. It is caused by mutations in the GAN gene, which codes for the gigaxonin protein. Gigaxonin plays a role in intermediate filament (IF) turnover [...] Read more.
Giant axonal neuropathy (GAN) is a pediatric, hereditary, neurodegenerative disorder that affects both the central and peripheral nervous systems. It is caused by mutations in the GAN gene, which codes for the gigaxonin protein. Gigaxonin plays a role in intermediate filament (IF) turnover hence loss of function of this protein leads to IF aggregates in various types of cells. These aggregates can lead to abnormal cellular function that manifests as a diverse set of symptoms in persons with GAN including nerve degeneration, cognitive issues, skin diseases, vision loss, and muscle weakness. GAN has no cure at this time. Currently, an adeno-associated virus (AAV) 9-mediated gene replacement therapy is being tested in a phase I clinical trial for the treatment of GAN. This review paper aims to provide an overview of giant axonal neuropathy and the current efforts at developing a treatment for this devastating disease. Full article
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35 pages, 1785 KiB  
Review
Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders
by Cintia Gomez Limia, Megan Baird, Maura Schwartz, Smita Saxena, Kathrin Meyer and Nicolas Wein
J. Pers. Med. 2022, 12(12), 1979; https://doi.org/10.3390/jpm12121979 - 30 Nov 2022
Cited by 3 | Viewed by 4868
Abstract
Neurodegenerative disorders (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and [...] Read more.
Neurodegenerative disorders (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood–brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient’s immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases. Full article
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16 pages, 1241 KiB  
Review
The Cellular and Molecular Signature of ALS in Muscle
by Ekene Anakor, William John Duddy and Stephanie Duguez
J. Pers. Med. 2022, 12(11), 1868; https://doi.org/10.3390/jpm12111868 - 08 Nov 2022
Cited by 7 | Viewed by 2384
Abstract
Amyotrophic lateral sclerosis is a disease affecting upper and lower motor neurons. Although motor neuron death is the core event of ALS pathology, it is increasingly recognized that other tissues and cell types are affected in the disease, making potentially major contributions to [...] Read more.
Amyotrophic lateral sclerosis is a disease affecting upper and lower motor neurons. Although motor neuron death is the core event of ALS pathology, it is increasingly recognized that other tissues and cell types are affected in the disease, making potentially major contributions to the occurrence and progression of pathology. We review here the known cellular and molecular characteristics of muscle tissue affected by ALS. Evidence of toxicity in skeletal muscle tissue is considered, including metabolic dysfunctions, impaired proteostasis, and deficits in muscle regeneration and RNA metabolism. The role of muscle as a secretory organ, and effects on the skeletal muscle secretome are also covered, including the increase in secretion of toxic factors or decrease in essential factors that have consequences for neuronal function and survival. Full article
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15 pages, 893 KiB  
Review
Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas
by Mohammed Khamaysa and Pierre-François Pradat
J. Pers. Med. 2022, 12(10), 1601; https://doi.org/10.3390/jpm12101601 - 28 Sep 2022
Cited by 10 | Viewed by 3793
Abstract
Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA [...] Read more.
Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA is riluzole, with a modest effect on survival. In this opinion view paper, we will discuss how to address some challenges for drug development in ALS at the conceptual, technological, and methodological levels. In addition, socioeconomic and ethical issues related to the legitimate need of patients to benefit quickly from new treatments will also be addressed. In conclusion, this brief review takes a more optimistic view, given the recent approval of two new drugs in some countries and the development of targeted gene therapies. Full article
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25 pages, 3720 KiB  
Review
Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation
by Javad Sharifi-Rad, Simona Rapposelli, Simona Sestito, Jesús Herrera-Bravo, Alejandra Arancibia-Diaz, Luis A. Salazar, Balakyz Yeskaliyeva, Ahmet Beyatli, Gerardo Leyva-Gómez, Carlos González-Contreras, Eda Sönmez Gürer, Miquel Martorell and Daniela Calina
J. Pers. Med. 2022, 12(9), 1515; https://doi.org/10.3390/jpm12091515 - 15 Sep 2022
Cited by 18 | Viewed by 4852
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a tangle-shaped accumulation of beta-amyloid peptide fragments and Tau protein in brain neurons. The pathophysiological mechanism involves the presence of Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response. This review aims [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a tangle-shaped accumulation of beta-amyloid peptide fragments and Tau protein in brain neurons. The pathophysiological mechanism involves the presence of Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response. This review aims to offer an updated compendium of the most recent and promising advances in AD treatment through the administration of phytochemicals. The literature survey was carried out by electronic search in the following specialized databases PubMed/Medline, Embase, TRIP database, Google Scholar, Wiley, and Web of Science regarding published works that included molecular mechanisms and signaling pathways targeted by phytochemicals in various experimental models of Alzheimer’s disease in vitro and in vivo. The results of the studies showed that the use of phytochemicals against AD has gained relevance due to their antioxidant, anti-neuroinflammatory, anti-amyloid, and anti-hyperphosphorylation properties of Tau protein. Some bioactive compounds from plants have been shown to have the ability to prevent and stop the progression of Alzheimer’s. Full article
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17 pages, 1383 KiB  
Review
The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases
by Gavin McCluskey, Colette Donaghy, Karen E. Morrison, John McConville, William Duddy and Stephanie Duguez
J. Pers. Med. 2022, 12(9), 1418; https://doi.org/10.3390/jpm12091418 - 30 Aug 2022
Cited by 6 | Viewed by 4678
Abstract
Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to [...] Read more.
Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration. Full article
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19 pages, 1715 KiB  
Review
Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?
by Hugo Alarcan, Yara Al Ojaimi, Debora Lanznaster, Jean-Michel Escoffre, Philippe Corcia, Patrick Vourc’h, Christian R. Andres, Charlotte Veyrat-Durebex and Hélène Blasco
J. Pers. Med. 2022, 12(7), 1071; https://doi.org/10.3390/jpm12071071 - 29 Jun 2022
Cited by 9 | Viewed by 1968
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies. Full article
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19 pages, 931 KiB  
Review
FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?
by Charis L. Himeda and Peter L. Jones
J. Pers. Med. 2022, 12(6), 865; https://doi.org/10.3390/jpm12060865 - 25 May 2022
Cited by 4 | Viewed by 4733
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead [...] Read more.
Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of DUX4 in skeletal muscle. The complex nature of the locus and the fact that FSHD is a toxic, gain-of-function disease present unique challenges for the design of therapeutic strategies. There are three major DUX4-targeting avenues of therapy for FSHD: small molecules, oligonucleotide therapeutics, and CRISPR-based approaches. Here, we evaluate the preclinical progress of each avenue, and discuss efforts being made to overcome major hurdles to translation. Full article
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