Loss Of Motor Neurons Research Articles

Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy

Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a “reverse” split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.

The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.MethodsWe used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.ResultsAPG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.ConclusionsOur results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.Graphical

Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1G93A mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.

Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes

Background/Objectives: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets. Methods: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis. Results: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex. Conclusions: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.

Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models.Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1G93A ALS mice, thereby establishing its therapeutic profile.F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca2+]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level.Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.

Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1G93A (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.

MicroRNAs as Biomarkers in Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic cause, gene-targeted therapies have been developed, aiming to increase SMN production in SMA patients. The SMN protein is likely involved in the synthesis of microRNAs (miRNAs), and dysregulated miRNA expression is increasingly associated with the pathophysiology of SMA. Currently, there is a lack of reliable biomarkers to monitor SMA; therefore, the search for novel SMA biomarkers, including miRNAs, is crucial as reliable tools are needed to track disease progression, predict the response to therapy and understand the different clinical outcomes of available treatments. In this review, we compile data on miRNAs associated with SMA pathogenesis and their potential use as biomarkers. Based on current knowledge, the most frequently deregulated miRNAs between SMA patients and controls, as well as pre- and post-treatment in SMA patients, include miR-1-3p, miR-133a-3p, miR-133b, and miR-206. These findings offer promising possibilities for improving patient classification and monitoring disease progression and response to treatment. Additionally, these findings provide insights into the broader molecular mechanisms and networks of SMA that could inform the development of future therapeutic strategies.

Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.

Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.

Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.

Gasdermin D is activated but does not drive neurodegeneration in SOD1 G93A model of ALS: Implications for targeting pyroptosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 G93A mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1 G93A animals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1 G93A mice onto a GSDMD - deficient background. In comparing SOD1 G93A ; Gsdmd +/+ and SOD1 G93A ; Gsdmd -/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1 G93A mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.

A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1G86R mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.

The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy

Manganese (Mn2+) is among the indispensable trace elements required by the human body, but high-dose Mn2+ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn2+ has been established for normal individuals in different countries. However, whether the UL of Mn2+ is suitable for the patients of Parkinson's disease (PD) is unclear.Here, we found unexpectedly that the dietary UL of Mn2+ supplement enhanced mitophagy through the PINK1/parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn2+ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn2+ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or cyclosporine A), abolished the neuroprotective effects of Mn2+.These findings demonstrate that the dietary UL of Mn2+ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn2+ intake.

A reassessment of spinal cord pathology in severe infantile spinal muscular atrophy: Reassessment of spinal cord pathology.

Spinal muscular atrophy (SMA) is a life-limiting paediatric motor neuron disease characterised by lower motor neuron loss, skeletal muscle atrophy and respiratory failure, if untreated. Revolutionary treatments now extend patient survival. However, a limited understanding of the foundational neuropathology challenges the evaluation of therapeutic success. As opportunities to study treatment-naïve tissue decrease, we have characterised spinal cord pathology in severe infantile SMA using gold-standard techniques, providing a baseline to measure treatment success and therapeutic limitations. Detailed histological analysis, stereology and transmission electron microscopy were applied to post-mortem spinal cord from severe infantile SMA patients to estimate neuron number at the end of life; characterise the morphology of ventral horn, lateral horn and Clarke's column neuron populations; assess cross-sectional spinal cord area; and observe myelinated white matter tracts in the clinically relevant thoracic spinal cord. Ventral horn neuron loss was substantial in all patients, even the youngest cases. The remaining ventral horn neurons were small with abnormal, occasionally chromatolytic morphology, indicating cellular damage. In addition to ventral horn pathology, Clarke's column sensory-associated neurons displayed morphological features of cellular injury, in contrast to the preserved sympathetic lateral horn neurons. Cellular changes were associated with aberrant development of grey and white matter structures that affected the overall dimensions of the spinal cord. We provide robust quantification of the neuronal deficit found at the end of life in SMA spinal cord. We question long-accepted dogmas of SMA pathogenesis and shed new light on SMA neuropathology out with the ventral horn, which must be considered in future therapeutic design.

Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients. This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded. 203 ALS patients had a mean age of onset equal 39years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2years with IQR of (1-4years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12 ± (6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76 ± 0.51. Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.

Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.

Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.

An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre–mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted “restored” at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis.

Neurological Aspects of Sarcopenia: A Comprehensive Update on Pathophysiology, Diagnosis, and Therapeutic Advances

Sarcopenia is an age-related disorder characterized by progressive and generalized loss of skeletal muscle tissue. This condition affects approximately 9.9-40.4% of older adults, 2-34% of outpatients, and about 56% of hospitalized patients. Sarcopenia is classified into primary and secondary types, with primary sarcopenia resulting from the natural aging process and secondary sarcopenia caused by various factors such as sedentary lifestyle, disease, and nutrition. The pathophysiology of sarcopenia involves cellular mechanisms, including genetic alterations, telomere erosion, and proteostasis disruption. Mitochondrial dysfunction, epigenetic modifications, and metabolic factors also contribute to the condition. Neurological aspects, such as motor neuron loss and sodium channel dysfunction, play a crucial role in the development of sarcopenia. Prevention and treatment strategies include exercise interventions, nutritional strategies, and pharmacological interventions. Vitamin D supplementation, testosterone replacement therapy, and selective androgen receptor modulators (SARMs) are among the treatments explored. However, these treatments come with potential

Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032 ).

Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.