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 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.

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 Consumption of unregulated food items (false morels) and risk for neurodegenerative disease (amyotrophic lateral sclerosis)

2020 ◽  
pp. 94-99
Author(s):  
P.S. Spencer ◽  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Free Radicals ◽  
Environmental Factors ◽  
Neurodegenerative Disease ◽  
Strong Evidence ◽  
Western Europe ◽  
World War ◽  
Food Items ◽  
Sporadic Als ◽  
Lateral Sclerosis

Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.

Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110308
Author(s):  
Fahad Hassan Shah ◽  
Song Ja Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Major Gene ◽  
Dna Binding Protein ◽  
Chemical Affinity ◽  
Drug Candidates ◽  
Medicinal Compounds ◽  
Candidate Drug ◽  
Lateral Sclerosis

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.

scholarly journals Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons

2018 ◽  
Vol 4 (10) ◽  
pp. eaat5847 ◽  
Author(s):  
Tatsuya Osaki ◽  
Sebastien G. M. Uzel ◽  
Roger D. Kamm
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Unit ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Research Effort ◽  
Muscle Contractions ◽  
Drug Candidates ◽  
Chip Technology ◽  
Sporadic Als ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)–derived and light-sensitive channelrhodopsin-2–induced MN spheroids from a patient with sporadic ALS. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein–43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates.

scholarly journals Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis

Brain ◽  
2009 ◽  
Vol 133 (1) ◽  
pp. 105-116 ◽  
Author(s):  
Adam K. Walker ◽  
Manal A. Farg ◽  
Chris R. Bye ◽  
Catriona A. McLean ◽  
Malcolm K. Horne ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Protein Disulphide Isomerase ◽  
Lateral Sclerosis

scholarly journals RNA-Binding Proteins in Amyotrophic Lateral Sclerosis and Neurodegeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Scott E. Ugras ◽  
James Shorter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disease ◽  
Rna Processing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Future Studies ◽  
Inclusion Formation ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurodegenerative disease, which is universally fatal. While the causes of this devastating disease are poorly understood, recent advances have implicated RNA-binding proteins (RBPs) that contain predicted prion domains as a major culprit. Specifically, mutations in the RBPs TDP-43 and FUS can cause ALS. Cytoplasmic mislocalization and inclusion formation are common pathological features of TDP-43 and FUS proteinopathies. Though these RBPs share striking pathological and structural similarities, considerable evidence suggests that the ALS-linked mutations in TDP-43 and FUS can cause disease by disparate mechanisms. In a recent study, Couthouis et al. screened for protein candidates that were also involved in RNA processing, contained a predicted prion domain, shared other phenotypic similarities with TDP-43 and FUS, and identified TAF15 as a putative ALS gene. Subsequent sequencing of ALS patients successfully identified ALS-linked mutations in TAF15 that were largely absent in control populations. This study underscores the important role that perturbations in RNA metabolism might play in neurodegeneration, and it raises the possibility that future studies will identify other RBPs with critical roles in neurodegenerative disease.

Sign in / Sign up

Export Citation Format

Share Document