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Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron...
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Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron Diseases

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Neuroscience".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 7122

Special Issue Editor

Dr. Matthew E.R. Butchbach

E-Mail Website
Guest Editor
1. Nemours Biomedical Research, Nemours Children’s Health Delaware, Wilmington, DE 19803, USA
2. Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
3. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, USA
Interests: motor neuron disease; neurogenetics; therapeutics discovery; rare diseases; translational neuroscience; spinal muscular atrophy; peripheral neuropathy; animal models

Special Issue Information

Dear Colleagues,

Motor neuron diseases affect the motor neurons projecting to or from the spinal cord and result in chronic and severe disability as well as early mortality. Many of these disorders have an onset during childhood. These diseases display clinical and genetic heterogeneity. While each specific motor neuron disease is classified as a rare disease, they collectively have a prevalence of about 1 in 700 live births. Due to recent advances in genomic sequencing and diagnostic assessment, we have made numerous advances in understanding the genetics underlying these disorders. These advances have also led to the development and characterization of multiple model systems for this group of disorders. These model systems have been instrumental. Furthermore, some diseases—such as spinal muscular atrophy and Pompe disease—have FDA-approved, disease-specific therapeutic options that generally need to be administered prior to the onset of or severe progression in disease.

While numerous advances have been made in understanding the genetics of early-onset, motor neuron diseases and in developing new therapeutic options, there are many disorders for which the genetics and molecular pathogenesis are not fully understood. The insights gathered from those disorders for which there are therapeutic options will be instrumental in guiding the molecular basis of these unresolved diseases. In order to gain a more comprehensive understanding of early-onset motor neuron diseases, we invite researchers at the forefront of this field to submit original and review articles on the topic of “Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron Diseases”. This Special Issue will provide valuable insights into these disorders for the scientific community, ranging from basic to translational to clinical researchers.

Dr. Matthew E.R. Butchbach
Guest Editor

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. Biology 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 2700 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

  • pediatrics
  • rare diseases
  • motor neuron disease
  • peripheral neuropathy
  • genetics
  • model systems
  • disease mechanisms
  • therapeutics discovery
  • diagnostics

Published Papers (3 papers)

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Research

22 pages, 2226 KiB  
Article
A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy
by Timothy J. Hines, Janice Bailey, Hedi Liu, Anyonya R. Guntur, Kevin L. Seburn, Samia L. Pratt, Jonathan R. Funke, Lisa M. Tarantino and Robert W. Burgess
Biology 2023, 12(7), 953; https://doi.org/10.3390/biology12070953 - 03 Jul 2023
Cited by 1 | Viewed by 1878
Abstract
Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria [...] Read more.
Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 MFN2 mutations are associated with a form of inherited peripheral neuropathy, Charcot–Marie–Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of Mfn2 (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, Mfn2L643P/L643P mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that Mfn2L643P causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology. Full article
(This article belongs to the Special Issue Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron Diseases)
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16 pages, 4426 KiB  
Article
In Vitro Modeling as a Tool for Testing Therapeutics for Spinal Muscular Atrophy and IGHMBP2-Related Disorders
by Julieth Andrea Sierra-Delgado, Shrestha Sinha-Ray, Abuzar Kaleem, Meysam Ganjibakhsh, Mohini Parvate, Samantha Powers, Xiaojin Zhang, Shibi Likhite and Kathrin Meyer
Biology 2023, 12(6), 867; https://doi.org/10.3390/biology12060867 - 16 Jun 2023
Cited by 2 | Viewed by 2400
Abstract
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant mortality. The most common form of SMA is caused by mutations in the SMN1 gene, located on 5q (SMA). On the other hand, mutations in IGHMBP2 lead to a large disease spectrum [...] Read more.
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant mortality. The most common form of SMA is caused by mutations in the SMN1 gene, located on 5q (SMA). On the other hand, mutations in IGHMBP2 lead to a large disease spectrum with no clear genotype–phenotype correlation, which includes Spinal Muscular Atrophy with Muscular Distress type 1 (SMARD1), an extremely rare form of SMA, and Charcot–Marie–Tooth 2S (CMT2S). We optimized a patient-derived in vitro model system that allows us to expand research on disease pathogenesis and gene function, as well as test the response to the AAV gene therapies we have translated to the clinic. We generated and characterized induced neurons (iN) from SMA and SMARD1/CMT2S patient cell lines. After establishing the lines, we treated the generated neurons with AAV9-mediated gene therapy (AAV9.SMN (Zolgensma) for SMA and AAV9.IGHMBP2 for IGHMBP2 disorders (NCT05152823)) to evaluate the response to treatment. The iNs of both diseases show a characteristic short neurite length and defects in neuronal conversion, which have been reported in the literature before with iPSC modeling. SMA iNs respond to treatment with AAV9.SMN in vitro, showing a partial rescue of the morphology phenotype. For SMARD1/CMT2S iNs, we were able to observe an improvement in the neurite length of neurons after the restoration of IGHMBP2 in all disease cell lines, albeit to a variable extent, with some lines showing better responses to treatment than others. Moreover, this protocol allowed us to classify a variant of uncertain significance on IGHMBP2 on a suspected SMARD1/CMT2S patient. This study will further the understanding of SMA, and SMARD1/CMT2S disease in particular, in the context of variable patient mutations, and might further the development of new treatments, which are urgently needed. Full article
(This article belongs to the Special Issue Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron Diseases)
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22 pages, 5906 KiB  
Article
Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy
by Albano Pinto, Catarina Cunha, Raquel Chaves, Matthew E. R. Butchbach and Filomena Adega
Biology 2022, 11(6), 824; https://doi.org/10.3390/biology11060824 - 27 May 2022
Cited by 2 | Viewed by 2119
Abstract
Transposable elements (TEs) are interspersed repetitive and mobile DNA sequences within the genome. Better tools for evaluating TE-derived sequences have provided insights into the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease [...] Read more.
Transposable elements (TEs) are interspersed repetitive and mobile DNA sequences within the genome. Better tools for evaluating TE-derived sequences have provided insights into the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene but retention of its nearly perfect orthologue SMN2. Both genes are highly enriched in TEs. To establish a link between TEs and SMA, we conducted a comprehensive, in silico analysis of TE insertions within the SMN1/2 loci of SMA, carrier and healthy genomes. We found an Alu insertion in the promoter region and one L1 element in the 3′UTR that may play an important role in alternative promoter as well as in alternative transcriptional termination. Additionally, several intronic Alu repeats may influence alternative splicing via RNA circularization and causes the presence of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that could lead to SMN1 exons deletions and, ultimately, SMA. TE characterization of the SMA genomic region could provide for a better understanding of the implications of TEs on human disease and genomic evolution. Full article
(This article belongs to the Special Issue Genomics, Phenotypic Characterization and Therapeutics Development for Early-Onset Motor Neuron Diseases)
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