New Insights into Genetic Neurological Diseases

A special issue of Neurology International (ISSN 2035-8377).

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 10573

Special Issue Editors


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Guest Editor
1. Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
2. Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Charcot–Marie–Tooth diseases; Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies; frontotemporal dementia
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Laboratory of Ion Channel Pathophysiology, Doshisha University Graduate School of Brain Science, Kyotanabe, Kyoto 610-0394, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies

E-Mail Website
Guest Editor
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Charcot–Marie–Tooth diseases; Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies; frontotemporal dementia

Special Issue Information

Dear Colleagues, 

Significant advances in next-generation nucleic acid sequencing systems have revealed the causes of many neurological disorders and their syndromes due to previously unexpected mutations in protein-encoding genes and non-coding RNAs. In addition, it has been determined familial mutations and fragility mutations in prominent neurological diseases such as Alzheimer’s disease and Parkinson’s disease, as well as tumors derived from ectoderm,  cause these diseases or increase the possibility of developing pathological conditions. Therefore, in this Special Issue, research on the gene mutations and fragility mutations related to the causes of new human neurological diseases, how these gene mutations lead to diseases, or new therapeutic methods for neurological diseases caused by existing mutations will be focused on in vitro studies and reviews using cell lines and disease-derived cells, and in vivo studies and reviews that clarify using experimental animals such as flies, zebrafish, and mice. However, not limited to the scope of these studies, we would like to cover a wide range of research on hereditary mutations.

Prof. Dr. Junji Yamauchi
Dr. Tomohiro Torii
Dr. Yuki Miyamoto
Guest Editors

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Keywords

  • genetic mutation
  • hereditary disease
  • neuropathy
  • in vitro
  • in vivo
  • mechanism of action
  • therapeutic procedure
  • intracellular signaling
  • extracellular signaling

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Published Papers (5 papers)

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Research

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14 pages, 2588 KiB  
Article
UBL3 Interacts with PolyQ-Expanded Huntingtin Fragments and Modifies Their Intracellular Sorting
by Soho Oyama, Hengsen Zhang, Rafia Ferdous, Yuna Tomochika, Bin Chen, Shuyun Jiang, Md. Shoriful Islam, Md. Mahmudul Hasan, Qing Zhai, A. S. M. Waliullah, Yashuang Ping, Jing Yan, Mst. Afsana Mimi, Chi Zhang, Shuhei Aramaki, Yusuke Takanashi, Tomoaki Kahyo, Yoshio Hashizume, Daita Kaneda and Mitsutoshi Setou
Neurol. Int. 2024, 16(6), 1175-1188; https://doi.org/10.3390/neurolint16060089 - 22 Oct 2024
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Abstract
Background/Objectives: UBL3 (Ubiquitin-like 3) is a protein that plays a crucial role in post-translational modifications, particularly in regulating protein transport within small extracellular vesicles. While previous research has predominantly focused on its interactions with α-synuclein, this study investigates UBL3’s role in Huntington’s disease [...] Read more.
Background/Objectives: UBL3 (Ubiquitin-like 3) is a protein that plays a crucial role in post-translational modifications, particularly in regulating protein transport within small extracellular vesicles. While previous research has predominantly focused on its interactions with α-synuclein, this study investigates UBL3’s role in Huntington’s disease (HD). HD is characterized by movement disorders and cognitive impairments, with its pathogenesis linked to toxic, polyglutamine (polyQ)-expanded mutant huntingtin fragments (mHTT). However, the mechanisms underlying the interaction between UBL3 and mHTT remain poorly understood. Methods: To elucidate this relationship, we performed hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) on postmortem brain tissue from HD patients. Gaussia princeps-based split-luciferase complementation assay and co-immunoprecipitation were employed to confirm the interaction between UBL3 and mHTT. Additionally, we conducted a HiBiT lytic detection assay to assess the influence of UBL3 on the intracellular sorting of mHTT. Finally, immunocytochemical staining was utilized to validate the colocalization and distribution of these proteins. Results: Our findings revealed UBL3-positive inclusions in the cytoplasm and nuclei of neurons throughout the striatum of HD patients. We discovered that UBL3 colocalizes and interacts with mHTT and modulates its intracellular sorting. Conclusions: These results suggest that UBL3 may play a significant role in the interaction and sorting of mHTT, contributing to the understanding of its potential implications in the pathophysiology of Huntington’s disease. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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12 pages, 505 KiB  
Article
Precision Dopaminergic Treatment in a Cohort of Parkinson’s Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review
by Christos Koros, Athina-Maria Simitsi, Nikolaos Papagiannakis, Anastasia Bougea, Roubina Antonelou, Ioanna Pachi, Evangelos Sfikas, Evangelia Stanitsa, Efthalia Angelopoulou, Vasilios C. Constantinides, Sokratis G. Papageorgiou, Constantin Potagas, Maria Stamelou and Leonidas Stefanis
Neurol. Int. 2024, 16(4), 833-844; https://doi.org/10.3390/neurolint16040062 - 30 Jul 2024
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Abstract
Introduction: Parkinson’s disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Methods: Demographic and treatment data of a cohort [...] Read more.
Introduction: Parkinson’s disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Methods: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. Results: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152–1810) in PRKN carriers and 765 ± 96.6 (range 660–850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. Conclusions: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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12 pages, 1212 KiB  
Article
Nusinersen Treatment for Spinal Muscular Atrophy: Retrospective Multicenter Study of Pediatric and Adult Patients in Kuwait
by Asma AlTawari, Mohammad Zakaria, Walaa Kamel, Nayera Shaalan, Gamal Ahmed Ismail Elghazawi, Mohamed Esmat Anwar Ali, Dalia Salota, Amr Attia, Ehab Elsayed Ali Elanay, Osama Shalaby, Fatema Alqallaf, Vesna Mitic and Laila Bastaki
Neurol. Int. 2024, 16(3), 631-642; https://doi.org/10.3390/neurolint16030047 - 4 Jun 2024
Cited by 1 | Viewed by 1465
Abstract
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is [...] Read more.
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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Review

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30 pages, 3208 KiB  
Review
Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy
by Lakshmi Krishna, Akila Prashant, Yogish H. Kumar, Shasthara Paneyala, Siddaramappa J. Patil, Shobha Chikkavaddaragudi Ramachandra and Prashant Vishwanath
Neurol. Int. 2024, 16(4), 731-760; https://doi.org/10.3390/neurolint16040055 - 5 Jul 2024
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Abstract
Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically [...] Read more.
Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically the absence or reduced expression of dystrophin. Gene replacement therapies, such as exon skipping, readthrough, and gene editing technologies, show promise in restoring dystrophin expression. Adeno-associated viruses (AAVs), a recent advancement in viral vector-based gene therapies, have shown encouraging results in preclinical and clinical studies. Secondary therapies aim to maintain muscle function and improve quality of life by mitigating DMD symptoms and complications. Glucocorticoid drugs like prednisone and deflazacort have proven effective in slowing disease progression and delaying loss of ambulation. Supportive treatments targeting calcium dysregulation, histone deacetylase, and redox imbalance are also crucial for preserving overall health and function. Additionally, the review includes a detailed table of ongoing and approved clinical trials for DMD, exploring various therapeutic approaches such as gene therapies, exon skipping drugs, utrophin modulators, anti-inflammatory agents, and novel compounds. This highlights the dynamic research field and ongoing efforts to develop effective DMD treatments. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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16 pages, 1275 KiB  
Review
New Insights into Risk Genes and Their Candidates in Multiple Sclerosis
by Remina Shirai and Junji Yamauchi
Neurol. Int. 2023, 15(1), 24-39; https://doi.org/10.3390/neurolint15010003 - 29 Dec 2022
Cited by 4 | Viewed by 2907
Abstract
Oligodendrocytes are central nervous system glial cells that wrap neuronal axons with their differentiated myelin membranes as biological insulators. There has recently been an emerging concept that multiple sclerosis could be triggered and promoted by various risk genes that appear likely to contribute [...] Read more.
Oligodendrocytes are central nervous system glial cells that wrap neuronal axons with their differentiated myelin membranes as biological insulators. There has recently been an emerging concept that multiple sclerosis could be triggered and promoted by various risk genes that appear likely to contribute to the degeneration of oligodendrocytes. Despite the known involvement of vitamin D, immunity, and inflammatory cytokines in disease progression, the common causes and key genetic mechanisms remain unknown. Herein, we focus on recently identified risk factors and risk genes in the background of multiple sclerosis and discuss their relationships. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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