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29 pages, 7017 KiB

Open AccessArticle

Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach

by Wonphorn Kandhavivorn, Hannes Glaß, Thomas Herrmannsdörfer, Tobias M. Böckers, Marc Uhlarz, Jonas Gronemann, Richard H. W. Funk, Jens Pietzsch, Arun Pal and Andreas Hermann

Cells 2023, 12(11), 1502; https://doi.org/10.3390/cells12111502 - 29 May 2023

Cited by 1 | Viewed by 4085

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range trafficking routes for organelles, cargo, mRNA and secretion with a high energy effort to serve crucial neuronal functions. Impaired intracellular pathways implicated in ALS pathology comprise RNA metabolism, cytoplasmic protein aggregation, cytoskeletal integrity for organelle trafficking and maintenance of mitochondrial morphology and function, cumulatively leading to neurodegeneration. Current drug treatments only have marginal effects on survival, thereby calling for alternative ALS therapies. Exposure to magnetic fields, e.g., transcranial magnetic stimulations (TMS) on the central nervous system (CNS), has been broadly explored over the past 20 years to investigate and improve physical and mental activities through stimulated excitability as well as neuronal plasticity. However, studies of magnetic treatments on the peripheral nervous system are still scarce. Thus, we investigated the therapeutic potential of low frequency alternating current magnetic fields on cultured spinal motoneurons derived from induced pluripotent stem cells of FUS-ALS patients and healthy persons. We report a remarkable restoration induced by magnetic stimulation on axonal trafficking of mitochondria and lysosomes and axonal regenerative sprouting after axotomy in FUS-ALS in vitro without obvious harmful effects on diseased and healthy neurons. These beneficial effects seem to derive from improved microtubule integrity. Thus, our study suggests the therapeutic potential of magnetic stimulations in ALS, which awaits further exploration and validation in future long-term in vivo studies. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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18 pages, 3097 KiB

Open AccessArticle

Synchrotron-Based Fourier-Transform Infrared Micro-Spectroscopy of Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients Reveals a Unique Biomolecular Profile

by Tanja Dučić and Jan Christoph Koch

Cells 2023, 12(11), 1451; https://doi.org/10.3390/cells12111451 - 23 May 2023

Viewed by 1604

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with the most common adult-onset neurodegenerative disorder affecting motoneurons. Although disruptions in macromolecular conformation and homeostasis have been described in association with ALS, the underlying pathological mechanisms are still not completely understood, and unambiguous [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with the most common adult-onset neurodegenerative disorder affecting motoneurons. Although disruptions in macromolecular conformation and homeostasis have been described in association with ALS, the underlying pathological mechanisms are still not completely understood, and unambiguous biomarkers are lacking. Fourier Transform Infrared Spectroscopy (FTIR) of cerebrospinal fluid (CSF) is appealing to extensive interest due to its potential to resolve biomolecular conformation and content, as this approach offers a non-invasive, label-free identification of specific biologically relevant molecules in a few microliters of CSF sample. Here, we analyzed the CSF of 33 ALS patients compared to 32 matched controls using FTIR spectroscopy and multivariate analysis and demonstrated major differences in the molecular contents. A significant change in the conformation and concentration of RNA is demonstrated. Moreover, significantly increased glutamate and carbohydrates are found in ALS. Moreover, key markers of lipid metabolism are strongly altered; specifically, we find a decrease in unsaturated lipids and an increase in peroxidation of lipids in ALS, whereas the total amount of lipids compared to proteins is reduced. Our study demonstrates that FTIR characterization of CSF could represent a powerful tool for ALS diagnosis and reveals central features of ALS pathophysiology. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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26 pages, 4605 KiB

Open AccessArticle

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons

by Vitaly L. Zimyanin, Anna-Maria Pielka, Hannes Glaß, Julia Japtok, Dajana Großmann, Melanie Martin, Andreas Deussen, Barbara Szewczyk, Chris Deppmann, Eli Zunder, Peter M. Andersen, Tobias M. Boeckers, Jared Sterneckert, Stefanie Redemann, Alexander Storch and Andreas Hermann

Cells 2023, 12(10), 1352; https://doi.org/10.3390/cells12101352 - 9 May 2023

Cited by 2 | Viewed by 2503

Abstract

Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS [...] Read more.

Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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16 pages, 2667 KiB

Open AccessArticle

Differences in Cerebral Glucose Metabolism in ALS Patients with and without C9orf72 and SOD1 Mutations

by Joke De Vocht, Donatienne Van Weehaeghe, Fouke Ombelet, Pegah Masrori, Nikita Lamaire, Martijn Devrome, Hilde Van Esch, Mathieu Moisse, Michel Koole, Patrick Dupont, Koen Van Laere and Philip Van Damme

Cells 2023, 12(6), 933; https://doi.org/10.3390/cells12060933 - 18 Mar 2023

Cited by 7 | Viewed by 1877

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. In 10% of patients, the disorder runs in the family. Our aim was to study the impact of ALS-causing gene mutations on cerebral glucose metabolism. Between October 2010 [...] Read more.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. In 10% of patients, the disorder runs in the family. Our aim was to study the impact of ALS-causing gene mutations on cerebral glucose metabolism. Between October 2010 and October 2022, 538 patients underwent genetic testing for mutations with strong evidence of causality for ALS and ¹⁸F-2-fluoro-2-deoxy-D-glucose-PET (FDG PET), at University Hospitals Leuven. We identified 48 C9orf72-ALS and 22 SOD1-ALS patients. After propensity score matching, two cohorts of 48 and 21 matched sporadic ALS patients, as well as 20 healthy controls were included. FDG PET images were assessed using a voxel-based and volume-of-interest approach. We observed widespread frontotemporal involvement in all ALS groups, in comparison to healthy controls. The degree of relative glucose metabolism in SOD1-ALS in motor and extra-motor regions did not differ significantly from matched sporadic ALS patients. In C9orf72-ALS, we found more pronounced hypometabolism in the peri-rolandic region and thalamus, and hypermetabolism in the medulla extending to the pons, in comparison to matched sporadic ALS patients. Our study revealed C9orf72-dependent differences in glucose metabolism in the peri-rolandic region, thalamus, and brainstem (i.e., medulla, extending to the pons) in relation to matched sporadic ALS patients. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

Jump to: Research

0 pages, 1645 KiB

Open AccessReview

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

by Laura Tzeplaeff, Alexandra V. Jürs, Camilla Wohnrade and Antonia F. Demleitner

Cells 2024, 13(5), 452; https://doi.org/10.3390/cells13050452 - 5 Mar 2024

Cited by 1 | Viewed by 1736

Abstract

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be [...] Read more.

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 1339 KiB

Open AccessReview

The Ying and Yang of Hydrogen Sulfide as a Paracrine/Autocrine Agent in Neurodegeneration: Focus on Amyotrophic Lateral Sclerosis

by Alida Spalloni, Susanna de Stefano, Juliette Gimenez, Viviana Greco, Nicola B. Mercuri, Valerio Chiurchiù and Patrizia Longone

Cells 2023, 12(13), 1691; https://doi.org/10.3390/cells12131691 - 22 Jun 2023

Cited by 1 | Viewed by 1344

Abstract

Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (H₂S) in the Central Nervous System (CNS) have changed. Consequently, H₂S has been elected as the third gas transmitter, along with carbon monoxide [...] Read more.

Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (H₂S) in the Central Nervous System (CNS) have changed. Consequently, H₂S has been elected as the third gas transmitter, along with carbon monoxide and nitric oxide, and a number of studies have focused on its neuromodulatory and protectant functions in physiological conditions. The research on H₂S has highlighted its many facets in the periphery and in the CNS, and its role as a double-faced compound, switching from protective to toxic depending on its concentration. In this review, we will focus on the bell-shaped nature of H₂S as an angiogenic factor and as a molecule released by glial cells (mainly astrocytes) and non-neuronal cells acting on the surrounding environment (paracrine) or on the releasing cells themselves (autocrine). Finally, we will discuss its role in Amyotrophic Lateral Sclerosis, a paradigm of a neurodegenerative disease. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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33 pages, 1781 KiB

Open AccessReview

Current State and Future Directions in the Therapy of ALS

by Laura Tzeplaeff, Sibylle Wilfling, Maria Viktoria Requardt and Meret Herdick

Cells 2023, 12(11), 1523; https://doi.org/10.3390/cells12111523 - 31 May 2023

Cited by 13 | Viewed by 6502

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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24 pages, 1784 KiB

Open AccessReview

Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis

by Maximilian Vidovic, Lars Hendrik Müschen, Svenja Brakemeier, Gerrit Machetanz, Marcel Naumann and Sergio Castro-Gomez

Cells 2023, 12(5), 736; https://doi.org/10.3390/cells12050736 - 24 Feb 2023

Cited by 9 | Viewed by 8362

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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24 pages, 1461 KiB

Open AccessReview

TDP-43 Proteinopathy Specific Biomarker Development

by Isabell Cordts, Annika Wachinger, Carlo Scialo, Paul Lingor, Magdalini Polymenidou, Emanuele Buratti and Emily Feneberg

Cells 2023, 12(4), 597; https://doi.org/10.3390/cells12040597 - 12 Feb 2023

Cited by 5 | Viewed by 3670

Abstract

TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer’s dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life [...] Read more.

TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer’s dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. For therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Therapeutic Opportunities)

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