Editorial

2 pages, 163 KiB

Open AccessEditorial

Molecular Research on Amyotrophic Lateral Sclerosis

by Luisa Agnello and Marcello Ciaccio

Int. J. Mol. Sci. 2022, 23(20), 12069; https://doi.org/10.3390/ijms232012069 - 11 Oct 2022

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Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, lethal, and degenerative disease of motor neurons for which there is no treatment currently available [...] Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

Research

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14 pages, 4750 KiB

Open AccessArticle

Selenoprotein P Concentrations in the Cerebrospinal Fluid and Serum of Individuals Affected by Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment and Alzheimer’s Dementia

by Teresa Urbano, Marco Vinceti, Jessica Mandrioli, Annalisa Chiari, Tommaso Filippini, Roberta Bedin, Manuela Tondelli, Cecilia Simonini, Giovanna Zamboni, Misaki Shimizu and Yoshiro Saito

Int. J. Mol. Sci. 2022, 23(17), 9865; https://doi.org/10.3390/ijms23179865 - 30 Aug 2022

Cited by 11 | Viewed by 2548

Abstract

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case–control [...] Read more.

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case–control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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19 pages, 2302 KiB

Open AccessArticle

4-Phenylbutyric Acid (4-PBA) Derivatives Prevent SOD1 Amyloid Aggregation In Vitro with No Effect on Disease Progression in SOD1-ALS Mice

by Leenor Alfahel, Shirel Argueti-Ostrovsky, Shir Barel, Mahmood Ali Saleh, Joy Kahn, Salome Azoulay-Ginsburg, Ayelet Rothstein, Simon Ebbinghaus, Arie Gruzman and Adrian Israelson

Int. J. Mol. Sci. 2022, 23(16), 9403; https://doi.org/10.3390/ijms23169403 - 20 Aug 2022

Cited by 6 | Viewed by 2590

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, we investigated the potential therapeutic effect of C4 and C5, two derivatives of the chemical chaperone 4-phenylbutyric acid (4-PBA). By combining in vivo and in vitro techniques, we show that, although C4 and C5 successfully inhibited amyloid aggregation of recombinant mutant SOD1 in a dose-dependent manner, they failed to suppress the accumulation of misfolded SOD1. Moreover, C4 or C5 daily injections to SOD1^G93A mice following onset had no effect on either the accumulation of misfolded SOD1 or the neuroinflammatory response in the spinal cord and, consequently, failed to extend the survival of SOD1^G93A mice or to improve their motor symptoms. Finally, pharmacokinetic (PK) studies demonstrated that high concentrations of C4 and C5 reached the brain and spinal cord but only for a short period of time. Thus, our findings suggest that use of such chemical chaperones for ALS drug development may need to be optimized for more effective results. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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13 pages, 1408 KiB

Open AccessArticle

The Expression of Active CD11b Monocytes in Blood and Disease Progression in Amyotrophic Lateral Sclerosis

by Ozlem Yildiz, Johannes Schroth, Vittoria Lombardi, Valentina Pucino, Yoana Bobeva, Ping Kei Yip, Klaus Schmierer, Claudio Mauro, Timothy Tree, Sian Mari Henson and Andrea Malaspina

Int. J. Mol. Sci. 2022, 23(6), 3370; https://doi.org/10.3390/ijms23063370 - 21 Mar 2022

Cited by 7 | Viewed by 2558

Abstract

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) [...] Read more.

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCM—HR: 1.05, CI: 1.01–1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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15 pages, 1736 KiB

Open AccessArticle

The Involvement of RAGE and Its Ligands during Progression of ALS in SOD1 G93A Transgenic Mice

by Natalia Nowicka, Kamila Szymańska, Judyta Juranek, Kamila Zglejc-Waszak, Agnieszka Korytko, Michał Załęcki, Małgorzata Chmielewska-Krzesińska, Krzysztof Wąsowicz and Joanna Wojtkiewicz

Int. J. Mol. Sci. 2022, 23(4), 2184; https://doi.org/10.3390/ijms23042184 - 16 Feb 2022

Cited by 9 | Viewed by 2283

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive degeneration of upper and lower motor neurons that causes paralysis and muscle atrophy. The pathogenesis of the disease is still not elucidated. Receptor for Advanced Glycation End Product (RAGE) is [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive degeneration of upper and lower motor neurons that causes paralysis and muscle atrophy. The pathogenesis of the disease is still not elucidated. Receptor for Advanced Glycation End Product (RAGE) is a major component of the innate immune system and has implications in ALS pathogenesis. Multiple studies suggest the role of RAGE and its ligands in ALS. RAGE and its ligands are overexpressed in human and murine ALS motor neurons, astrocytes, and microglia. Here, we demonstrated the expression of RAGE and its ligands during the progression of the disease in the transgenic SOD1 G93A mouse lumbar spinal cord. We observed the highest expression of HMGB1 and S100b proteins at ALS onset. Our results highlight the potential role of RAGE and its ligands in ALS pathogenesis and suggest that some of the RAGE ligands might be used as biomarkers in early ALS diagnosis and potentially be useful in targeted therapeutic interventions at the early stage of this devastating disease. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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11 pages, 797 KiB

Open AccessArticle

Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress

by Benjamin E. Clarke, Bernadett Kalmar and Linda Greensmith

Int. J. Mol. Sci. 2022, 23(3), 1789; https://doi.org/10.3390/ijms23031789 - 04 Feb 2022

Cited by 6 | Viewed by 2303

Abstract

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here [...] Read more.

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis. In primary murine motor neurons, shRNA-mediated knockdown of TRAP1 expression results in mitochondrial dysfunction but does not further exacerbate damage induced by oxidative stress alone. Together, these results show that TRAP1 may be a potential therapeutic target for neurodegenerative diseases such as ALS, where mitochondrial dysfunction has been shown to be an early marker of pathogenesis. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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21 pages, 4407 KiB

Open AccessArticle

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

by Thibaut Burg, Elisabeth Rossaert, Matthieu Moisse, Philip Van Damme and Ludo Van Den Bosch

Int. J. Mol. Sci. 2021, 22(20), 11224; https://doi.org/10.3390/ijms222011224 - 18 Oct 2021

Cited by 24 | Viewed by 3046

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been [...] Read more.

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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15 pages, 1652 KiB

Open AccessArticle

Alterations in Leptin Signaling in Amyotrophic Lateral Sclerosis (ALS)

by Agueda Ferrer-Donato, Ana Contreras, Laura M. Frago, Julie A. Chowen and Carmen M. Fernandez-Martos

Int. J. Mol. Sci. 2021, 22(19), 10305; https://doi.org/10.3390/ijms221910305 - 24 Sep 2021

Cited by 10 | Viewed by 3162

Abstract

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, [...] Read more.

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin’s effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin’s actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43^A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43^A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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Review

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24 pages, 1114 KiB

Open AccessReview

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

by Bradley Roberts, Frances Theunissen, Francis L. Mastaglia, P. Anthony Akkari and Loren L. Flynn

Int. J. Mol. Sci. 2022, 23(16), 9364; https://doi.org/10.3390/ijms23169364 - 19 Aug 2022

Cited by 7 | Viewed by 3821

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with “synucleinopathy disorders”. We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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18 pages, 1167 KiB

Open AccessReview

Oxidative Stress in Amyotrophic Lateral Sclerosis: Synergy of Genetic and Environmental Factors

by Anca Motataianu, Georgiana Serban, Laura Barcutean and Rodica Balasa

Int. J. Mol. Sci. 2022, 23(16), 9339; https://doi.org/10.3390/ijms23169339 - 19 Aug 2022

Cited by 18 | Viewed by 3396

Abstract

Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. This review aims to describe the main processes influenced by the most frequent genetic mutations and environmental factors concurring in oxidative stress occurrence in ALS and the potential therapeutic molecules capable of diminishing the ALS related pro-oxidative status. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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14 pages, 1690 KiB

Open AccessReview

DnaJC7 in Amyotrophic Lateral Sclerosis

by Allison A. Dilliott, Catherine M. Andary, Meaghan Stoltz, Andrey A. Petropavlovskiy, Sali M. K. Farhan and Martin L. Duennwald

Int. J. Mol. Sci. 2022, 23(8), 4076; https://doi.org/10.3390/ijms23084076 - 07 Apr 2022

Cited by 10 | Viewed by 3747

Abstract

Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents [...] Read more.

Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin–proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones’ machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS. Full article

(This article belongs to the Special Issue Molecular Research on Amyotrophic Lateral Sclerosis)

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