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Metabolites
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Metabolic Dysfunction in Motor Neuron Disease
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Metabolic Dysfunction in Motor Neuron Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 22974

Special Issue Editors

Dr. Shyuan T. Ngo

E-Mail Website
Guest Editor
The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia
Interests: motor neuron disease; amyotrophic lateral sclerosis; energy metabolism; mitochondrial function; neuromuscular junction
Dr. Frederik J. Steyn

E-Mail Website
Guest Editor
School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia
Interests: neurodegenerative diease; motor neuron diseases; amyotrophic lateral sclerosis; systemic metabolism; metabolic dysfunction
Dr. Tesfaye Tefera

E-Mail Website
Guest Editor
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia
Interests: energy metabolism; mitochondrial function; motor neuron disease; neuro-glial metabolic interactions; metabolites; amino acids

Special Issue Information

Dear Colleagues,

Motor neuron diseases are a group of progressive neurological disorders in which motor neurons undergo degeneration and die. While a number of pathogenic mechanisms, including neuronal hyperexcitability, glutamate excitotoxicity, protein misfolding and aggregation, and oxidative stress have been proposed to contribute to the onset and progression of MND, the last decade has seen a growing number of studies highlighting the contribution of metabolic dysfunction to the disease.

The clinical significance of metabolic changes for disease progression in MND has remained largely unresolved. This Special Issue showcases a collection of original research and review articles that highlight the latest discoveries and advances in the field of metabolic dysfunction in MND. In improving our understanding of the metabolic physiology/biology of MND, there the is potential to facilitate new knowledge about the disease that will lead to the identification or development of novel metabolically directed therapies that can improve outcomes for people living with MND.

Dr. Shyuan T. Ngo
Dr. Frederik J. Steyn
Dr. Tesfaye Tefera
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. Metabolites 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

  • Motor neuron disease
  • Amyotrophic lateral sclerosis
  • Energy metabolism
  • Mitochondria
  • Neuron
  • Skeletal muscle

Published Papers (7 papers)

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Research

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19 pages, 18316 KiB  
Article
Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis
by Gemma L. Sadler, Katherine N. Lewis, Vinod K. Narayana, David P. De Souza, Joel Mason, Catriona McLean, David G. Gonsalvez, Bradley J. Turner and Samantha K. Barton
Metabolites 2022, 12(6), 554; https://doi.org/10.3390/metabo12060554 - 17 Jun 2022
Cited by 5 | Viewed by 3136
Abstract
Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its [...] Read more.
Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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14 pages, 2418 KiB  
Article
Body Weight Gain Is Associated with the Disease Stage in Advanced Amyotrophic Lateral Sclerosis with Invasive Ventilation
by Yuki Nakayama, Toshio Shimizu, Chiharu Matsuda, Michiko Haraguchi, Kentaro Hayashi, Kota Bokuda, Masahiro Nagao, Akihiro Kawata and Kazushi Takahashi
Metabolites 2022, 12(2), 191; https://doi.org/10.3390/metabo12020191 - 19 Feb 2022
Cited by 3 | Viewed by 1831
Abstract
We investigated the incidence of weight gain and its related factors in patients with amyotrophic lateral sclerosis (ALS) who underwent tracheostomy and invasive ventilation (TIV). Seventy-eight patients with ALS and TIV were enrolled and followed up prospectively. We clarified the clinical profiles of [...] Read more.
We investigated the incidence of weight gain and its related factors in patients with amyotrophic lateral sclerosis (ALS) who underwent tracheostomy and invasive ventilation (TIV). Seventy-eight patients with ALS and TIV were enrolled and followed up prospectively. We clarified the clinical profiles of patients with increased weight following TIV and examined chronological variations in their body mass index (BMI), energy intake, and serum albumin levels. Post follow-up, we determined their disease stage according to their communication impairment (stage I to V) and investigated factors associated with BMI increase following TIV. Patients with a post-TIV BMI increase ≥1.86 kg/m2 demonstrated a higher incidence of ophthalmoplegia (76.2%), total quadriplegia (61.9%), severe communication impairment (stage V; 33.3%), and hypoalbuminemia than those with a BMI increase <1.86 kg/m2. Patients with stage V communication impairment exhibited a larger and faster BMI decrease before TIV (mean −4.2 kg/m2 and −2.5 kg/m2/year, respectively); a larger BMI increase (mean +4.6 kg/m2) following TIV, despite lower energy intake; and lower albumin levels post follow-up than those with lower-stage communication impairment. Multilevel linear regression analysis demonstrated an independent association between communication impairment stages (stage V) and a post-TIV BMI increase (p = 0.030). Weight gain and hypoalbuminemia during TIV in patients with ALS were associated with the disease stage and may be attributable to the neurodegenerative processes that are peculiar to ALS. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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17 pages, 2963 KiB  
Article
2-Year-Old and 3-Year-Old Italian ALS Patients with Novel ALS2 Mutations: Identification of Key Metabolites in Their Serum and Plasma
by Mukesh Gautam, Renata Del Carratore, Benjamin Helmold, Alessandra Tessa, Oge Gozutok, Navdeep Chandel, Halil Idrisoglu, Paolo Bongioanni, Roberta Battini and P.Hande Ozdinler
Metabolites 2022, 12(2), 174; https://doi.org/10.3390/metabo12020174 - 12 Feb 2022
Cited by 3 | Viewed by 3752
Abstract
Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense [...] Read more.
Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense need to reveal the underlying causes of the disease and to identify potential biomarkers. To shed light onto the metabolomic events that are perturbed with respect to ALS2 mutations, we investigated the metabolites present in the serum and plasma of a three-year-old female patient (AO) harboring pathogenic variants in ALS2, together with her relatives, healthy male and female controls, as well as another two-year-old patient DH, who had mutations at different locations and domains of ALS2. Serum and plasma samples were analyzed with a quantitative metabolomic approach to reveal the identity of metabolites present in serum and plasma. This study not only shed light onto the perturbed cellular pathways, but also began to reveal the presence of a distinct set of key metabolites that are selectively present or absent with respect to ALS2 mutations, laying the foundation for utilizing metabolites as potential biomarkers for a subset of ALS. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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10 pages, 12959 KiB  
Article
TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS
by Suvithanandhini Loganathan, Bryce A. Wilson, Sara B. Carey, Ernesto Manzo, Archi Joardar, Berrak Ugur and Daniela C. Zarnescu
Metabolites 2022, 12(2), 101; https://doi.org/10.3390/metabo12020101 - 21 Jan 2022
Cited by 5 | Viewed by 3247
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a Drosophila model of ALS based on TDP-43 expression in motor neurons that recapitulates hallmark features of motor neuron disease including TDP-43 aggregation, locomotor dysfunction, and reduced lifespan. To gain insights into metabolic changes caused by TDP-43, we performed global metabolomic profiling in larvae expressing TDP-43 (WT or ALS associated mutant variant, G298S) and identified significant alterations in several metabolic pathways. Here, we report alterations in multiple metabolic pathways and highlight upregulation of Tricarboxylic acid (TCA) cycle metabolites and defects in neurotransmitter levels. We also show that modulating TCA cycle flux either genetically or by dietary intervention mitigates TDP-43-dependent locomotor defects. In addition, dopamine levels are significantly reduced in the context of TDP-43G298S, and we find that treatment with pramipexole, a dopamine agonist, improves locomotor function in vivo in Drosophila models of TDP-43 proteinopathy. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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Review

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29 pages, 2013 KiB  
Review
Altered TDP-43 Structure and Function: Key Insights into Aberrant RNA, Mitochondrial, and Cellular and Systemic Metabolism in Amyotrophic Lateral Sclerosis
by Leanne Jiang and Shyuan T. Ngo
Metabolites 2022, 12(8), 709; https://doi.org/10.3390/metabo12080709 - 29 Jul 2022
Cited by 10 | Viewed by 4528
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets—particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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20 pages, 1096 KiB  
Review
Metabolic Dysfunction in Motor Neuron Disease: Shedding Light through the Lens of Autophagy
by Subhavi De Silva, Bradley J. Turner and Nirma D. Perera
Metabolites 2022, 12(7), 574; https://doi.org/10.3390/metabo12070574 - 22 Jun 2022
Cited by 2 | Viewed by 2456
Abstract
Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context [...] Read more.
Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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23 pages, 830 KiB  
Review
Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
by Niccolò Candelise, Illari Salvatori, Silvia Scaricamazza, Valentina Nesci, Henri Zenuni, Alberto Ferri and Cristiana Valle
Metabolites 2022, 12(3), 233; https://doi.org/10.3390/metabo12030233 - 09 Mar 2022
Cited by 9 | Viewed by 2723
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Motor Neuron Disease)
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