Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches

Neurological Sciences, Год журнала: 2024, Номер 45(9), С. 4121 - 4131

Опубликована: Апрель 27, 2024

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons severe skeletal muscle atrophy. The etiology ALS linked to muscle, which can activate retrograde signaling cascade destroys neurons. This why satellite cells mitochondria play crucial role health performance muscles. review presents current knowledge on involvement mitochondrial dysfunction, atrophy, cells, junction (NMJ) ALS. It also discusses therapeutic strategies, including exercise, drugs, stem gene therapy, prospective use transplantation as viable strategy.

Язык: Английский

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Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Июль 9, 2024

The pathophysiology of ALS involves many signs a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as important physiological functions are performed by cuproenzymes. While it unsurprising that symptoms related to deficiency, resulting vascular, antioxidant system mitochondrial oxidative respiration deficiencies, there also toxicity such ROS generation enhanced protein aggregation. We discuss how plays key role proteostasis interacts either directly or indirectly the aggregate-prone proteins implicated ALS, TDP-43, C9ORF72, SOD1 FUS well effect their aggregation on homeostasis. suggest loss cuproprotein function at core pathology, condition driven combination unbound can initiate and/or accelerate could trigger positive feedback cycle whereby aggregates other chain reaction eventually captures elements proteostatic mechanisms place counteract them. end result an abundance aggregated non-functional cuproproteins chaperones alongside depleted intracellular stores, general lack cuproenzyme function. then possible aetiology illustrate strong risk factors including environmental toxins BMAA heavy metals functionally behave promote disturb metabolism drives this vicious sporadic ALS. From synthesis, we propose restoration balance using delivery agents chaperones/chaperone mimetics, perhaps conjunction neuroprotective amino acid serine, promising strategy treatment incurable disease.

Язык: Английский

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From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders

Biology, Год журнала: 2024, Номер 13(9), С. 719 - 719

Опубликована: Сен. 12, 2024

Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's (PD), primarily affect the central nervous system, leading to progressive neuronal loss motor cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe wasting as result of neuron degeneration, well alterations gene expression, protein aggregation, oxidative stress. Muscle atrophy mitochondrial dysfunction are observed AD, which may exacerbate decline due systemic metabolic dysregulation. PD patients exhibit fiber atrophy, altered composition, α-synuclein aggregation within cells, contributing symptoms progression. Systemic inflammation impaired degradation pathways common among disorders, highlighting key player Understanding muscle-related changes offers potential therapeutic avenues, such targeting function, reducing inflammation, promoting regeneration with exercise pharmacological interventions. This review emphasizes importance considering an integrative approach neurodegenerative research, both peripheral pathological mechanisms, order develop more effective treatments improve patient outcomes.

Язык: Английский

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Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 872 - 872

Опубликована: Янв. 21, 2025

Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) transgenic SOD1-G93A mouse physiology were built using the first-principles-based first-order feedback framework dynamic meta-analysis with parameter optimization. Two in silico developed: a WT model to simulate normal homeostasis ALS pathology their response treatments. The simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, proteomics curated data from published experiments. Temporal measures (rotarod, grip strength, body weight) used validation. Results illustrate untreated cannot maintain due mathematical oscillating instability as determined by eigenvalue analysis. onset magnitude homeostatic corresponded progression. Oscillations associated high gain hypervigilant regulation. Multiple combination treatments stabilized near-normal homeostasis. However, timing effect size critical stabilization corresponding therapeutic success. dynamics-based approach redefines strategies emphasizing restoration through precisely timed stabilizing therapies, presenting promising application other neurodegenerative diseases.

Язык: Английский

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Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2025, Номер 1871(4), С. 167707 - 167707

Опубликована: Фев. 6, 2025

Язык: Английский

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Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 4, 2024

SUMMARY ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain spinal cord, cortical frontal lobe. Although pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, nuclear abnormalities as drivers neuronal death. In this study, we show loss envelope (NE) integrity a key pathology associated with pore (NPC) injury C9ORF72 mutant neurons. Importantly, mechanical stresses generated by cytoskeletal forces on NE can lead to NPC injury, integrity, accumulation damage. demonstrate restoring tensional homeostasis, disconnecting nucleus from cytoskeleton, rescue reduce damage cells. Together, our data suggest modulation homeostasis repair may represent novel promising therapeutic target for ALS/FTD.

Язык: Английский

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Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 976 - 976

Опубликована: Янв. 12, 2024

Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and benefits through different mechanisms, such as secretion of neurotrophic factors, replacement, activation endogenous cells, decreased neuroinflammation. Several sources have proposed transplantation restoration damaged tissue. recent decades, intensive research focused on gestational novel resource therapy. The present review provides an update preclinical/clinical applications treatment protein-misfolding diseases including Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD) amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this therapeutic approach into clinical setting.

Язык: Английский

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Casein kinase 1 inhibitor avoids TDP-43 pathology propagation in a patient-derived cellular model of amyotrophic lateral sclerosis

Neurobiology of Disease, Год журнала: 2024, Номер 192, С. 106430 - 106430

Опубликована: Фев. 6, 2024

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without cure to reverse its progression. Its main hallmark the nuclear protein TDP-43, which undergoes different post-translational modifications leading loss of function in nucleus and an increase toxicity cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation various contexts. With aim advancing therapeutics focused on preventing pathology, we studied potential role lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines patients as source forms healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) recipient investigate seeding spread proteinopathy. Furthermore, evaluated targeting phosphorylation with CK-1 inhibitor prevent pathology. The results presented herein indicate are secreted into extracellular medium could be transported by vesicles, spreading pathology cells. Moreover, tunneling nanotubes also been discovered pathological may involved transport TDP-43. Interestingly, in-house designed (IGS2.7) was sufficient halt transmission, addition known effects restoring homeostasis patients-derived

Язык: Английский

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Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2024, Номер 1870(5), С. 167192 - 167192

Опубликована: Апрель 22, 2024

Several mutations in the SOD1 gene encoding for antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration patients' death within 2–5 years from diagnosis. Motor loss related symptomatology manifest mostly adult life and, to date, there is still gap of knowledge on precise cellular molecular events preceding neurodegeneration. To deepen our awareness early phases disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either mutation A4V or G85R human (hSOD1A4V hSOD1G85R). We demonstrate that pan-neuronal expression hSOD1A4V hSOD1G85R pathogenic construct impairs survival performance transgenic flies. Moreover, protein transcript analysis fly heads indicates mutant hSOD1 induction stimulates glial marker Repo, up-regulates IMD/Toll immune pathways through antimicrobial peptides interferes oxidative metabolism. Finally, cytological larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters found modulated timeframe when neurodegeneration not detected. The novelty work twofold: have expressed first time all neurons confirmed some ALS-related pathological phenotypes flies, confirming power generating ALS-like phenotypes. pathogenesis aberrations up-regulation. These findings were unexplored SOD1-ALS field.

Язык: Английский

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Amyotrophic Lateral Sclerosis (ALS) Type 8: A Narrative Review

Cureus, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Amyotrophic lateral sclerosis type 8 (ALS8) is a rare familial subtype of ALS caused by mutations in the vesicle-associated membrane protein-associated protein B (VAPB) gene, particularly p.P56S mutation. It distinguished slower disease progression and an earlier onset compared to sporadic forms, along with unique clinical features such as severe cramping, fasciculations, postural tremors, cognitive behavioral impairments. Although current pharmacological options, riluzole, edaravone, sodium phenylbutyrate/taurursodiol, provide modest benefits, they fail address underlying genetic mechanisms ALS8. Emerging gene therapies, RNA-based interventions, stem cell approaches hold promise for precision-targeted treatments but face challenges application. Symptom management strategies, including respiratory, nutritional, psychological support, are crucial improving patient outcomes quality life. Despite significant progress understanding molecular pathogenesis ALS8, its rarity, phenotypic variability, limited data pose therapeutic advancements. This narrative review highlights trajectory potential pathways innovative, subtype-specific emphasizing need multidisciplinary targeted optimize care this distinct subtype.

Язык: Английский

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