scholarly journals Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?

2019 ◽  
Vol 20 (11) ◽  
pp. 2759 ◽  
Author(s):  
Laura Moreno-Martinez ◽  
Ana Cristina Calvo ◽  
María Jesús Muñoz ◽  
Rosario Osta
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Animal Models ◽  
Motor Neuron ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Inflammatory Cytokines ◽  
Potential Application ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis ◽  
Circulating Cytokines

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown alterations in levels of numerous cytokines in ALS, supporting the contribution of neuroinflammation to the progressive motor neuron loss. However, none of them is fully sensitive and specific enough to become a universal biomarker for ALS. This review gathers the numerous circulating cytokines that have been found dysregulated in both ALS animal models and patients. Particularly, it highlights the opposing results found in the literature to date, and points out another potential application of inflammatory cytokines as therapeutic targets.

scholarly journals Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

2021 ◽  
Vol 22 (22) ◽  
pp. 12236
Author(s):  
Tiziana Bonifacino ◽  
Roberta Arianna Zerbo ◽  
Matilde Balbi ◽  
Carola Torazza ◽  
Giulia Frumento ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Animal Models ◽  
Motor Neuron ◽  
Gene Mutations ◽  
Genetic Mutations ◽  
Future Perspectives ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

scholarly journals Mitophagy Modulation, a New Player in the Race against ALS

2021 ◽  
Vol 22 (2) ◽  
pp. 740
Author(s):  
Enrique Madruga ◽  
Inés Maestro ◽  
Ana Martínez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Unknown Etiology ◽  
Drug Candidates ◽  
Relevant Evidence ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

scholarly journals Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Junmei Wang ◽  
Lydia Tierney ◽  
Ranjeet Mann ◽  
Thomas Lonsway ◽  
Chandler L. Walker
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Lumbar Spinal Cord ◽  
Therapeutic Effects ◽  
Spinal Cord Tissue ◽  
Neuron Loss ◽  
Neuroprotective Therapy ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 μg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.

Longitudinal study of functional spinal alpha motor neuron loss in amyotrophic lateral sclerosis

2002 ◽  
Vol 25 (4) ◽  
pp. 520-526 ◽  
Author(s):  
K. Arasaki ◽  
Y. Kato ◽  
A. Hyodo ◽  
R. Ushijima ◽  
M. Tamaki
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Longitudinal Study ◽  
Motor Neuron ◽  
Neuron Loss ◽  
Motor Neuron Loss ◽  
Alpha Motor Neuron ◽  
Lateral Sclerosis

scholarly journals Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. 89-93 ◽  
Author(s):  
Silas Maniatis ◽  
Tarmo Äijö ◽  
Sanja Vickovic ◽  
Catherine Braine ◽  
Kristy Kang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Early Time ◽  
Course Of Disease ◽  
Molecular Events ◽  
Motor Neuron Loss ◽  
Als Patients ◽  
Lateral Sclerosis

Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.

scholarly journals Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

2019 ◽  
Author(s):  
Roy Maimon ◽  
Lior Ankol ◽  
Romana Weissova ◽  
Elizabeth Tank ◽  
Tal Gradus Pery ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Complex Formation ◽  
Neuromuscular Junction ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Molecular Mechanism ◽  
Motor Neurons ◽  
Axon Degeneration ◽  
Destabilizing Factors ◽  
Lateral Sclerosis

AbstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with selective dysfunction; it causes the death of motor neurons (MNs). In spite of some progress, currently no effective treatment is available for ALS. Before such treatment can be developed, a more thorough understanding of ALS pathogenesis is required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS pathology via secretion of destabilizing factors such as Sema3A; these factors trigger axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on the molecular mechanism by which muscle contribute to MNs loss in ALS. We identified CRMP4 as part of a retrograde death signal generated in response to muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1G93A) and human-derived (C9orf72) ALS models. Introducing peptides that interfere with CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN loss in ALS.SummaryMaimon et al. identify a novel retrograde death mechanism that contribute to MN loss in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the axon.

Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis

2017 ◽  
Vol 128 (3) ◽  
pp. 495-500 ◽  
Author(s):  
Christoph Neuwirth ◽  
Paul E. Barkhaus ◽  
Christian Burkhardt ◽  
José Castro ◽  
David Czell ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Unit ◽  
Neuron Loss ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

Motor unit number index and neurophysiological index as candidate biomarkers of presymptomatic motor neuron loss in amyotrophic lateral sclerosis

2018 ◽  
Vol 58 (2) ◽  
pp. 204-212 ◽  
Author(s):  
Marcio Luiz Escorcio‐Bezerra ◽  
Agessandro Abrahao ◽  
Karlo Faria Nunes ◽  
Nadia Iandoli De Oliveira Braga ◽  
Acary Souza Bulle Oliveira ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Unit ◽  
Neuron Loss ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis
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