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Genes Jun 2024Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs-macrophage communication is pivotal. Here, we focus on extracellular vesicle (EVS)-mediated communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. mSOD1 NSC-34 cells release a high number of vesicles, both large-lEVs (300 nm diameter) and small-sEVs (90 nm diameter), containing inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN degeneration.
Topics: Animals; Extracellular Vesicles; Mice; RAW 264.7 Cells; Superoxide Dismutase-1; Macrophages; Amyotrophic Lateral Sclerosis; Motor Neurons; Inflammation; Mutation; Transfection; Humans
PubMed: 38927671
DOI: 10.3390/genes15060735 -
Genes May 2024Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of (c.86A>G) in one of the probands. This finding is significant as mutations in the gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring mutations. In conclusion, our study contributes to the growing body of evidence linking to ALS and enhances our understanding of the intricate genetic landscape of this disease.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Amyotrophic Lateral Sclerosis; China; East Asian People; Kinesins; Mutation; Mutation, Missense; Pedigree; Phenotype; Whole Genome Sequencing
PubMed: 38927616
DOI: 10.3390/genes15060680 -
Biomedicines Jun 2024Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a...
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ-tetrahydrocannabinol in L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of , and genes, which are known to suppress the cell cycle. , , , , , , , , , , , , , , , and genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis.
PubMed: 38927547
DOI: 10.3390/biomedicines12061340 -
Biomedicines May 2024Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several...
Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.
PubMed: 38927369
DOI: 10.3390/biomedicines12061162 -
Biomolecules Jun 2024One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the... (Review)
Review
One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.
Topics: Humans; Parkinson Disease; Animals; Neurons; Nerve Degeneration; Glutathione Transferase; Neuroprotective Agents; Disease Models, Animal; Antiparkinson Agents
PubMed: 38927076
DOI: 10.3390/biom14060673 -
ENeuro Jun 2024Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by...
Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extra-sensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in Dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) projecting CT neurons located in lower L6a than VPm-only projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements. Layer 6 corticothalamic (L6 CT) feedback circuits are ubiquitous across mammalian species and modalities, and their activities have a strong influence on thalamic excitability and information throughput to the neocortex. Despite clear evidence of CT effects on the thalamus, we know relatively little about how CT cells themselves are regulated. Our results show that input from the primary motor cortex strongly excites a subclass of CT neurons in the primary somatosensory cortex that innervate both core and higher-order somatosensory nuclei rather than those exclusively targeting core somatosensory thalamus. The cortico-cortico-thalamic pathway formed by these connections establishes a circuit-level substrate for supporting CT influence operating under the guidance of ongoing motor activities.
PubMed: 38926084
DOI: 10.1523/ENEURO.0255-24.2024 -
Aging Cell Jun 2024The molecular mechanisms underlying age-related declines in learning and long-term memory are still not fully understood. To address this gap, our study focused on...
The molecular mechanisms underlying age-related declines in learning and long-term memory are still not fully understood. To address this gap, our study focused on investigating the transcriptional landscape of a singularly identified motor neuron L7 in Aplysia, which is pivotal in a specific type of nonassociative learning known as sensitization of the siphon-withdraw reflex. Employing total RNAseq analysis on a single isolated L7 motor neuron after short-term or long-term sensitization (LTS) training of Aplysia at 8, 10, and 12 months (representing mature, late mature, and senescent stages), we uncovered aberrant changes in transcriptional plasticity during the aging process. Our findings specifically highlight changes in the expression of messenger RNAs (mRNAs) that encode transcription factors, translation regulators, RNA methylation participants, and contributors to cytoskeletal rearrangements during learning and long noncoding RNAs (lncRNAs). Furthermore, our comparative gene expression analysis identified distinct transcriptional alterations in two other neurons, namely the motor neuron L11 and the giant cholinergic neuron R2, whose roles in LTS are not yet fully elucidated. Taken together, our analyses underscore cell type-specific impairments in the expression of key components related to learning and memory within the transcriptome as organisms age, shedding light on the complex molecular mechanisms driving cognitive decline during aging.
PubMed: 38924663
DOI: 10.1111/acel.14228 -
Cell Reports Jun 2024During behavior, the motor cortex sends copies of motor-related signals to sensory cortices. Here, we combine closed-loop behavior with large-scale physiology,...
During behavior, the motor cortex sends copies of motor-related signals to sensory cortices. Here, we combine closed-loop behavior with large-scale physiology, projection-pattern-specific recordings, and circuit perturbations to show that neurons in mouse secondary motor cortex (M2) encode sensation and are influenced by expectation. When a movement unexpectedly produces a sound, M2 becomes dominated by sound-evoked activity. Sound responses in M2 are inherited partially from the auditory cortex and are routed back to the auditory cortex, providing a path for the reciprocal exchange of sensory-motor information during behavior. When the acoustic consequences of a movement become predictable, M2 responses to self-generated sounds are selectively gated off. These changes in single-cell responses are reflected in population dynamics, which are influenced by both sensation and expectation. Together, these findings reveal the embedding of sensory and expectation signals in motor cortical activity.
PubMed: 38923464
DOI: 10.1016/j.celrep.2024.114396 -
Neural Regeneration Research Apr 2024Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where...
Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 1012 (×2), and then consecutive infusions of 7.5 × 1012 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.
PubMed: 38922880
DOI: 10.4103/NRR.NRR-D-23-01815 -
Metabolites May 2024Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on... (Review)
Review
Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene.
PubMed: 38921437
DOI: 10.3390/metabo14060302