Special Issue "Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 20 July 2023 | Viewed by 10768

Special Issue Editor

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Interests: amyotrophic lateral sclerosis; animal models; immune system; peripheral nervous system; skeletal muscle

Special Issue Information

Dear Colleagues,

Over the past twenty years, we have seen a dramatic increase in knowledge of Amyotrophic Lateral Sclerosis. Using animal and in vitro models has allowed for the identification of several mechanisms that contribute to motor neuron (MN) injury. It has emerged that certain aspects of ALS are non-cell-autonomous and that other cell types within the spinal cord, and peripheral immune system, contribute to the progression of the disease. However, due to the multifaceted and multisystemic nature of the disease, several pathological aspects are still to be clarified.

In this Special Issue of Cells, I invite you to contribute in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of molecular mechanisms and targets that might spread out the therapeutic perspective in ALS. Expert articles describing ALS mechanistic, functional, cellular, biochemical, or general aspects are highly welcome.

Dr. Giovanni Nardo
Guest Editor

Manuscript Submission Information

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Keywords

  • amyotrophic lateral sclerosis
  • molecular mechanisms, in vivo and in vitro models
  • preclinical treatments
  • therapeutic targets

Published Papers (11 papers)

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Research

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Article
Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis
Cells 2023, 12(9), 1228; https://doi.org/10.3390/cells12091228 - 24 Apr 2023
Viewed by 822
Abstract
Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients and model systems like mice and yeast have helped in understanding the association of various signaling and metabolic pathways with the disease. The yeast model system has played a pivotal role in elucidating the gene amyloid interactions. We carried out an integrated transcriptomic and metabolomic analysis of the TDP-43 expressing yeast model to elucidate deregulated pathways associated with the disease. The analysis shows the deregulation of the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism. Transcriptomic analysis of GEO datasets of TDP-43 expressing motor neurons from mice models of ALS and ALS patients shows considerable overlap with experimental results. Furthermore, a yeast model was used to validate the obtained results using metabolite addition and gene knock-out experiments. Taken together, our result shows a potential role for the TCA cycle, cellular redox pathway, NAD metabolism, and fatty acid metabolism in disease. Supplementation of reduced glutathione, nicotinate, and the keto diet might help to manage the disease. Full article
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Article
Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
Cells 2023, 12(7), 1031; https://doi.org/10.3390/cells12071031 - 28 Mar 2023
Viewed by 1236
Abstract
Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients. Full article
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Article
Intramuscular IL-10 Administration Enhances the Activity of Myogenic Precursor Cells and Improves Motor Function in ALS Mouse Model
Cells 2023, 12(7), 1016; https://doi.org/10.3390/cells12071016 - 26 Mar 2023
Viewed by 1125
Abstract
Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, with a poor prognosis, a highly unmet therapeutic need, and a burden on health care costs. Hitherto, strategies aimed at protecting motor neurons have missed or modestly delayed ALS due to [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, with a poor prognosis, a highly unmet therapeutic need, and a burden on health care costs. Hitherto, strategies aimed at protecting motor neurons have missed or modestly delayed ALS due to a failure in countering the irreversible muscular atrophy. We recently provided direct evidence underlying the pivotal role of macrophages in preserving skeletal muscle mass. Based on these results, we explored whether the modulation of macrophage muscle response and the enhancement of satellite cell differentiation could effectively promote the generation of new myofibers and counteract muscle dysfunction in ALS mice. For this purpose, disease progression and the survival of SOD1G93A mice were evaluated following IL-10 injections in the hindlimb skeletal muscles. Thereafter, we used ex vivo methodologies and in vitro approaches on primary cells to assess the effect of the treatment on the main pathological signatures. We found that IL-10 improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of macrophages. This resulted in delayed muscle atrophy and motor neuron loss. Our findings provide the basis for a suitable adjunct multisystem therapeutic approach that pinpoints a primary role of muscle pathology in ALS. Full article
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Article
Development of a Nanoparticle-Based Approach for the Blood–Brain Barrier Passage in a Murine Model of Amyotrophic Lateral Sclerosis
Cells 2022, 11(24), 4003; https://doi.org/10.3390/cells11244003 - 10 Dec 2022
Viewed by 977
Abstract
The development of nanoparticles (NPs) to enable the passage of drugs across blood–brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, [...] Read more.
The development of nanoparticles (NPs) to enable the passage of drugs across blood–brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, we investigated whether the functionalization of avidin-nucleic-acid-nanoassembly (ANANAS) with apolipoprotein E (ApoE) would allow BBB passage in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Our results demonstrated that ANANAS was able to transiently cross BBB to reach the central nervous system (CNS), and ApoE did not enhance this property. Next, we investigated if ANANAS could improve CNS drug delivery. To this aim, the steroid dexamethasone was covalently linked to ANANAS through an acid-reversible hydrazone bond. Our data showed that the steroid levels in CNS tissues of SOD1G93A mice treated with nanoformulation were below the detection limit. This result demonstrates that the passage of BBB is not sufficient to guarantee the release of the cargo in CNS and that a different strategy for drug tethering should be devised. The present study furthermore highlights that NPs can be useful in improving the passage through biological barriers but may limit the interaction of the therapeutic compound with the specific target. Full article
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Article
Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS
Cells 2022, 11(23), 3923; https://doi.org/10.3390/cells11233923 - 04 Dec 2022
Cited by 3 | Viewed by 1379
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes’ neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1G93A astrocytes with single miRNA mimics reduced astrocytes’ activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes’ reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS. Full article
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Article
Evaluation of the Hematological and Serum Biochemistry Parameters in the Pre-Symptomatic and Symptomatic Stages of ALS Disease to Support Early Diagnosis and Prognosis
Cells 2022, 11(22), 3569; https://doi.org/10.3390/cells11223569 - 11 Nov 2022
Viewed by 751
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Since there are no pathognomonic tests for ALS prognoses; clinical diagnoses of the disease take time and are usually difficult. Prognostic biomarkers are urgently needed for rapid and effective ALS prognoses. Male [...] Read more.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Since there are no pathognomonic tests for ALS prognoses; clinical diagnoses of the disease take time and are usually difficult. Prognostic biomarkers are urgently needed for rapid and effective ALS prognoses. Male albino rats were divided into ten groups based on age: 0 (40–45 days old), A (70–75 days old), B (90–95 days old), C (110–115 days old), and D (130–135 days old). Each group was divided into two subgroups according to its mutation status: wild type (SOD1WT) or mutated (SOD1G93A). Serum biochemistry and hematological parameters were measured in 90 rats to evaluate possible biomarkers for faster ALS diagnoses and prognoses. Weight loss, cholesterol, creatinine, glucose, total bilirubin (TBIL), blood urine nitrogen (BUN), c-peptide, glucagon, PYY, white blood cell (WBC), lymphocyte (LYM), monocyte (MID), granulocyte (GRAN), red cell distribution width with standard deviation (RDW-SD), red cell distribution width with the coefficient of variation (RDW-CV), platelet (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and procalcitonin (PCT) levels were changed in the SOD1G93A rats compared to the SOD1WT rats independently from aging. For the first time in the literature, we showed promising hematological and serum biochemistry parameters in the pre-symptomatic and symptomatic stages of ALS by eliminating the effects of aging. Our results can be used for early diagnoses and prognoses of ALS, improving the quality of life and survival time of ALS patients. Full article
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Review

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Review
Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets
Cells 2023, 12(10), 1443; https://doi.org/10.3390/cells12101443 - 22 May 2023
Viewed by 400
Abstract
Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, [...] Read more.
Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca2+ influx through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing. Full article
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Review
Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis
Cells 2023, 12(9), 1302; https://doi.org/10.3390/cells12091302 - 02 May 2023
Viewed by 907
Abstract
Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones’ involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS. Full article
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Review
Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis
Cells 2023, 12(8), 1188; https://doi.org/10.3390/cells12081188 - 19 Apr 2023
Viewed by 396
Abstract
Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic [...] Read more.
Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform. Full article
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Review
Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications
Cells 2023, 12(8), 1180; https://doi.org/10.3390/cells12081180 - 18 Apr 2023
Viewed by 540
Abstract
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical [...] Read more.
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the “fit-for-purpose” concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status. Full article
Review
Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity
Cells 2023, 12(6), 957; https://doi.org/10.3390/cells12060957 - 21 Mar 2023
Viewed by 995
Abstract
Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood [...] Read more.
Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Characterization of a novel long non-coding RNA in the antisense direction of SOD1 gene
Authors: Camilla Bernardini
Affiliation: Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

Title: How Protein Quality Control Mechanism Can Serve as a Therapeutics Strategy Against the Pathomechanism of Amyotrophic Lateral Sclerosis Neurodegeneration
Authors: Yuvraj Anandrao Jagtap; Prashant Kumar; Ankur Rakesh Dubey; Sumit Kinger; Akash Choudhary; Amit Mishra*
Affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, 342037, Rajasthan, India

Title: Vascularisation of the motorcortex as a target for the development of new prevention and therapy strategies in ALS
Authors: Stefanie Schreiber
Affiliation: Helen Wills Neuroscience Institute, 132 Barker Hall, Mail Code 3190, University of California, Berkeley, CA 94720
Abstract: In ALS, vascular brain health seems to be of pivotal importance for protection from disease and slowing of the disease course. Indeed, ALS patients commonly suffer from cerebrovascular disease, vascular risk and cerebral small vessel alterations. Subsequent restricted vascular brain health exerts its detrimental effects on motoneurons through impaired endothelial cell formation caused by VEGF lowering, which in turn promotes blood-brain barrier leaks and inflammation. Reduced pericyte coverage further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview about the mechanistic underpinnings of impaired vascular brain health in ALS giving a roadmap how cutting-edge magnetic resonance imaging can help for its detection. We discuss fingerprints of motorcortex supply through more or less branches from the anterior and middle cerebral artery as a marker of vascular resistance and resilience against downstream effects of vascular risk and events in ALS. We further outline how certain lifestyle modifications adapted to the patients’ needs and capabilities have the potential to mechanistically target the brain’s microvasculature and in that advertise for rethinking ALS clinical trials and management.

Title: Pathological insights from different Amyotrophic Lateral Sclerosis animal models
Authors: Longhong Zhu, Shihua Li, Xiao-Jiang Li* and Peng Yin*
Affiliation: Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.

Title: Mutations in SLC22A5 and DHTKD1 genes may lead to ALS by affecting mitochondrial metabolism
Authors: Giuseppe ARENA
Affiliation: Luxembourg Centre for Systems Biomedicine (LCSB); UNIVERSITY OF LUXEMBOURG CAMPUS BELVAL; 6, Avenue du Swing; L-4367 Esch-sur-Alzette

Title: Correcting mitochondrial dysdynamism in ALS
Authors: Gerald W Dorn II
Affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA

Title: Regulation of innate immune dysfunction as a therpy for ALS
Authors: Michael S. McGrath
Affiliation: Department of Medicine Suite 207, Bldg 3, ZSFG. 1001 Potrero Ave. San Francisco, CA. 94110 650-347-1258

Title: Towards the characterization of TDP-43 functional role(s) in cellular models exposed to ALS-related stress
Authors: Manuel Portero-Otin
Affiliation: Instituto de Investigación Biomédica de Lleida Fundación Dr. Pifarré, Lleida, Spain
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease without disease-modifying treatments. Despite its clinical and pathophysiological heterogeneity, transactive response DNA-binding protein of 43 kDa (TDP-43) could link some of the disease hallmarks including impairment of RNA, protein and energetic homeostasis and oxidative stress. In this work, we hypothesized that dysregulation in TDP-43, can be modelled in cellular systems, leading to changes in sensitivity in front of ALS-related stress stimuli. We exposed the human cell line HeLa expressing an inducible silencing system to knock down the expression of TDP-43 to energetic and proteostasis stress and evaluated the effects on essential traits of cell homeostasis, including cell viability, oxygen consumption, and cell death. Results indicate TDP-43-dependent differences in basal cell metabolism, oxygen consumption and viability, but also in response to proteasome inhibitors and oxidative stress. In addition, HeLa cells were susceptible to the loss of function of TDP-43. We could not specify a single cell death mechanism since we found evidence supporting different pathways simultaneously. All in all, these results highlight the relevance of TDP-43 for maintaining cellular homeostasis and the use of proposed cellular models as a platform for screening relevant pathogenic pathways related to ALS and possible therapeutic targets.

Title: Biofluid biomarkers in amyotrophic lateral sclerosis prognosis: a review of recent developments and their applications in therapeutic translation
Authors: Daniel Sánchez-Tejerina1,2, Arnau Llauradó 1,2, Javier Sotoca 1,2, Verónica Lopez-Diego 1,2, María Salvadó 1,2, JM Vidal-Taboada 2, Raúl Juntas 1,2
Affiliation: 1. Neuromuscular Diseases Unit, European Reference Network on Rare Neuromuscular Diseases (ERN EURO-NMD), Neurology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, European Reference Network for Neuromuscular and Rare Diseases EURO-NMD, 08035 Barcelona, Spain 2. Peripheral Nervous System Research Group. Vall d´Hebron Research Institut (VHIR). 08035 Barcelona, Spain

Title: Aggregation propensity does not predict neurotoxicity of pathogenic mutations in the ubiquitin adaptor protein, UBQLN2
Authors: Nathaniel Safren1,3*, Elizabeth Thuy Dao2, Harihar Miligunar Mohan3, Camellia Huang3, Bryce Trotter3, Carlos Castañeda2, Hank Paulson3,4, Sami Barmada3, Lisa M Sharkey3,4 *
Affiliation: 1. Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 2. Departments of Biology and Chemistry, Syracuse University, Syracuse, NY 13244 3. Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200 4. Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109-2200
Abstract: The ubiquitin-adaptor protein UBQLN2 promotes degradation of multiple aggregate-prone proteins implicated in neurodegenerative diseases inclu­­­ding huntingtin, tau and a-synuclein. Missense mutations in UBQLN2 are also known to directly cause neurodegenerative disease along the ALS/FTD spectrum. Previously we demonstrated that the properties of UBQLN2 liquid-like molecular assemblies are altered by a specific pathogenic mutation, P506T, and that UBQLN2 aggregation propensity correlated with neurotoxicity. Building on this work, here we systematically assess the effects of multiple, spatially separated ALS-linked missense mutations on the properties of UBQLN2. We measured the effects of UBQLN2 mutants A282V, M446R, P497S, P479H and P506T on aggregation propensity, neurotoxicity, phase separation, autophagic flux and ability to regulate levels of a known protein substrate. Unlike the P506T mutation, other tested UBQLN2-ALS mutants did not reveal a predictable correlation between aggregation propensity and neurotoxicity. These results emphasize that the mechanism by which pathogenic UBQLN2 mutations cause neurodegeneration is likely complex and not necessarily tied to aggregation propensity of the mutant protein.

Title: Genetic down regulation of the mglu5 receptor dampens the reactive and neurotoxic phenotype of spinal cord astrocytes cultured from late symptomatic SOD1G93A mice
Authors: Carola Torazza 1, Francesca Provenzano 1, Matilde Balbi 1, Maria Cerminara2, Tiziana Bonifacino 1,3, Elena Gallia 1, Arianna Roberta Zerbo 1, Silvia Ravera 4, Cesare Usai 5, Paolo Scudieri 2, Aldamari
Affiliation: 1 Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy; 2 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo, 316132 Genoa, Italy; 3 Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Pisa, 56122, Italy; 4 Department of Experimental Medicine (DIMES), University of Genoa, Via Alberti L.B. 2, 16132 Genova, Italy; 5 Institute of Biophysics, National Research Council (CNR), Via De Marini 6, 16149 Genoa, Italy; 6 UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italy; 7 Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, KU Leuven - University of Leuven, Leuven, 3000, Belgium. 8 VIB-Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, 3000, Belgium. 9 Ionis Pharmaceuticals, Carlsbad, California, USA. 10 IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy;

Title: ALS associated change in circular RNA and RNA editing
Authors: Takashi Hosaka
Affiliation: Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan University of Tsukuba Hospital/Jichi Medical University Joint Ibaraki Western Regional Clinical Education Center, Chikusei, Ibaraki, 308-0813, Japan

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