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Molecular Mechanism Underlying Rare Inherited Neurological Diseases
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Molecular Mechanism Underlying Rare Inherited Neurological Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 9566

Special Issue Editors

Dr. Agnieszka Ługowska

E-Mail Website1 Website2
Guest Editor
Institute of Psychiatry and Neurology, Department of Genetics, Warsaw, Poland
Interests: molecular and biochemical bases of lysosomal diseases; epidemiology of lysosomal diseases; development of novel diagnostic procedure; monitoring of treatment efficacy; biomarkers
Prof. Dr. Johannes Berger

E-Mail Website1 Website2 Website3
Guest Editor
Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria
Interests: peroxisomes; adrenoleukodystrophy; plasmalogens; ether-lipids; lipids in Alzheimer’s disease; peroxisomes in Alzheimer’s disease; adrenomyeloneuropathy; ABCD1; brain inflammation

Special Issue Information

Dear Colleagues,

A disease is considered rare when it affects less than one person in 2000 live births. Currently, about 6000 rare diseases are distinguished, but the awareness of medical and general society is still insufficient. Among these diseases are genetically inherited diseases related to various disorders of the nervous system. The molecular mechanisms underlying these diseases are differential. Some of them have a metabolic basis, such as lysosomal diseases, peroxisomal diseases, mitochondrial diseases, other metabolic leukodystrophies, disorders of metal metabolism, disturbances of vitamin metabolism, disturbances of neurotransmitter metabolism and many others. There is also a huge group of monogenic neurodegenerative and neuromuscular diseases. Recently, studies on oxidative stress and immune system response have displayed a great role in elucidating the bases of neurological diseases.

Due to often irreversible changes in the nervous system, therapies should be implemented at the very early stages of a disease. This leads to a demand for the development of reliable diagnostic methods to improve the efficacy of treatment.

In this Special Issue, we want to present the latest scientific achievements in the research on rare, genetically determined diseases that affect the nervous system. These studies are broad in nature and cover both molecular and cellular aspects. We focus on studies related to the explanation of pathomechanisms, diagnostics, those searching for new targeted treatment strategies and new biomarkers for the detection of patients, and the use of new research techniques.

Both original and review articles or communications providing new insights into the subject are welcomed.

Dr. Agnieszka Ługowska
Prof. Dr. Johannes Berger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • rare genetic diseases;
  • inherited metabolic diseases;
  • translational research;
  • proteomic research;
  • novel therapies for genetic metabolic diseases;
  • pathogenesis of disease;
  • molecular background of genetic diseases;
  • biochemical background of genetic diseases;
  • new approaches in research and diagnosis

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Published Papers (3 papers)

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Research

14 pages, 4672 KiB  
Article
Complex N-Linked Glycosylation: A Potential Modifier of Niemann–Pick Disease, Type C1 Pathology
by Niamh X. Cawley, Anna T. Lyons, Daniel Abebe, Rachel Luke, Julia Yerger, Rebecca Telese, Christopher A. Wassif, Joan E. Bailey-Wilson and Forbes D. Porter
Int. J. Mol. Sci. 2022, 23(9), 5082; https://doi.org/10.3390/ijms23095082 - 3 May 2022
Cited by 5 | Viewed by 2700
Abstract
Complex asparagine-linked glycosylation plays key roles in cellular functions, including cellular signaling, protein stability, and immune response. Previously, we characterized the appearance of a complex asparagine-linked glycosylated form of lysosome-associated membrane protein 1 (LAMP1) in the cerebellum of Npc1−/− mice. This LAMP1 [...] Read more.
Complex asparagine-linked glycosylation plays key roles in cellular functions, including cellular signaling, protein stability, and immune response. Previously, we characterized the appearance of a complex asparagine-linked glycosylated form of lysosome-associated membrane protein 1 (LAMP1) in the cerebellum of Npc1−/− mice. This LAMP1 form was found on activated microglia, and its appearance correlated both spatially and temporally with cerebellar Purkinje neuron loss. To test the importance of complex asparagine-linked glycosylation in NPC1 pathology, we generated NPC1 knock-out mice deficient in MGAT5, a key Golgi-resident glycosyl transferase involved in complex asparagine-linked glycosylation. Our results show that Mgat5−/−:Npc1−/− mice were smaller than Mgat5+/+:Npc1−/− mice, and exhibited earlier NPC1 disease onset and reduced lifespan. Western blot and lectin binding analyses of cerebellar extracts confirmed the reduction in complex asparagine-linked glycosylation, and the absence of the hyper-glycosylated LAMP1 previously observed. Western blot analysis of cerebellar extracts demonstrated reduced calbindin staining in Mgat5−/−:Npc1−/− mice compared to Mgat5+/+:Npc1−/− mutant mice, and immunofluorescent staining of cerebellar sections indicated decreased levels of Purkinje neurons and increased astrogliosis in Mgat5−/−:Npc1−/− mice. Our results suggest that reduced asparagine-linked glycosylation increases NPC1 disease severity in mice, and leads to the hypothesis that mutations in genes involved in asparagine-linked glycosylation may contribute to disease severity progression in individuals with NPC1. To examine this with respect to MGAT5, we analyzed 111 NPC1 patients for two MGAT5 SNPs associated with multiple sclerosis; however, we did not identify an association with NPC1 phenotypic severity. Full article
(This article belongs to the Special Issue Molecular Mechanism Underlying Rare Inherited Neurological Diseases)
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10 pages, 1355 KiB  
Article
Complex Transposon Insertion as a Novel Cause of Pompe Disease
by Igor Bychkov, Galina Baydakova, Alexandra Filatova, Ochir Migiaev, Andrey Marakhonov, Nataliya Pechatnikova, Ekaterina Pomerantseva, Fedor Konovalov, Maria Ampleeva, Vladimir Kaimonov, Mikhail Skoblov and Ekaterina Zakharova
Int. J. Mol. Sci. 2021, 22(19), 10887; https://doi.org/10.3390/ijms221910887 - 8 Oct 2021
Cited by 9 | Viewed by 2815
Abstract
Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In [...] Read more.
Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In this article, we report a novel molecular genetic cause of Pompe disease, which could be hardly detected using routine molecular genetic analysis. Whole genome sequencing followed by comprehensive functional analysis allowed us to discover and characterize a complex mobile genetic element insertion deep in the intron 15 of the GAA gene in a patient with infantile onset Pompe disease. Full article
(This article belongs to the Special Issue Molecular Mechanism Underlying Rare Inherited Neurological Diseases)
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11 pages, 1804 KiB  
Article
Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing
by Igor Bychkov, Artur Galushkin, Alexandra Filatova, Andrey Nekrasov, Marina Kurkina, Galina Baydakova, Alexandra Ilyushkina, Mikhail Skoblov and Ekaterina Zakharova
Int. J. Mol. Sci. 2021, 22(8), 4154; https://doi.org/10.3390/ijms22084154 - 16 Apr 2021
Cited by 3 | Viewed by 3037
Abstract
It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants [...] Read more.
It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants have become an important object of genomic medicine. To improve the accuracy of variant interpretation in public mutation repositories, we applied the minigene splicing assay to study the effects of 24 variants that were predicted to affect normal splicing in the genes associated with propionic acidemia (PA)—PCCA and PCCB. As a result, 13 variants (including one missense and two synonymous variants) demonstrated a significant alteration of splicing with the predicted deleterious effect at the protein level and were characterized as spliceogenic loss-of-function variants. The analysis of the available data for the studied variants and application of the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines allowed us to precisely classify five of the variants and change the pathogenic status of nine. Using the example of the PA genes, we demonstrated the utility of the minigene splicing assay in the fast and effective assessment of the spliceogenic effect for identified variants and highlight the necessity of their standardized classification. Full article
(This article belongs to the Special Issue Molecular Mechanism Underlying Rare Inherited Neurological Diseases)
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