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Neural Regeneration Research Feb 2025JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs)...
Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury.
JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
PubMed: 38819069
DOI: 10.4103/NRR.NRR-D-23-01414 -
Frontiers in Molecular Neuroscience 2024The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual... (Review)
Review
The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual stimuli. A-kinase anchoring proteins (AKAPs), known for binding protein kinase A (PKA), contribute to the specificity and efficiency of retinal signaling. They play multifaceted roles in various retinal cell types, influencing photoreceptor sensitivity, neurotransmitter release in bipolar cells, and the integration of visual information in ganglion cells. AKAPs like AKAP79/150 and AKAP95 exhibit distinct subcellular localizations, impacting synaptic transmission and receptor sensitivity in photoreceptors and bipolar cells. Furthermore, AKAPs are involved in neuroprotective mechanisms and axonal degeneration, particularly in retinal ganglion cells. In particular, AKAP6 coordinates stress-specific signaling and promotes neuroprotection following optic nerve injury. As our review underscores the therapeutic potential of targeting AKAP signaling complexes for retinal neuroprotection and enhancement, it acknowledges challenges in developing selective drugs that target complex protein-protein interactions. Overall, this exploration of AKAPs provides valuable insights into the intricacies of retinal signaling, offering a foundation for understanding and potentially addressing retinal disorders.
PubMed: 38813437
DOI: 10.3389/fnmol.2024.1412407 -
Acta Neuropathologica Communications May 2024Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the...
Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the axon and transported back to the soma. This transport is essential since the final degradation of the vesicular content occurs only close to or in the soma. Here, we established an in vivo live-imaging model in the rat optic nerve using viral vector mediated LC3-labeling and two-photon-microscopy to analyze axonal transport of AVs. Under basal conditions in vivo, 50% of the AVs are moving with a majority of 85% being transported in the retrograde direction. Transport velocity is higher in the retrograde than in the anterograde direction. A crush lesion of the optic nerve results in a rapid breakdown of retrograde axonal transport while the anterograde transport stays intact over several hours. Close to the lesion site, the formation of AVs is upregulated within the first 6 h after crush, but the clearance of AVs and the levels of lysosomal markers in the adjacent axon are reduced. Expression of p150Glued, an adaptor protein of dynein, is significantly reduced after crush lesion. In vitro, fusion and colocalization of the lysosomal marker cathepsin D with AVs are reduced after axotomy. Taken together, we present here the first in vivo analysis of axonal AV transport in the mammalian CNS using live-imaging. We find that axotomy leads to severe defects of retrograde motility and a decreased clearance of AVs via the lysosomal system.
Topics: Animals; Axonal Transport; Optic Nerve; Rats; Autophagy; Optic Nerve Injuries; Male; Axons; Nerve Degeneration; Rats, Sprague-Dawley; Female
PubMed: 38812004
DOI: 10.1186/s40478-024-01791-2 -
Vision (Basel, Switzerland) May 2024Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical... (Review)
Review
Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.
PubMed: 38804352
DOI: 10.3390/vision8020031 -
Cureus Apr 2024Guillain-Barré syndrome (GBS) refers to a spectrum of acute immune-mediated polyradiculoneuropathies, among which is acute motor axonal neuropathy (AMAN), which is...
Guillain-Barré syndrome (GBS) refers to a spectrum of acute immune-mediated polyradiculoneuropathies, among which is acute motor axonal neuropathy (AMAN), which is typified by predominant motor involvement and axonal degeneration. This case study describes the presentation, diagnosis, and physiotherapy management using virtual reality-based technology in a 29-year-old male patient with AMAN. Nerve conduction velocity testing was used to diagnose motor axonal neuropathy in the patient, who had weakness subsequent to gastrointestinal symptoms. Intravenous immunoglobulin therapy was started, and a physiotherapy protocol was planned for eight weeks according to the patient's functional status. Physiotherapy plays an important role in the rehabilitation of patients with GBS, addressing the specific motor deficits and promoting recovery. The aim was to improve muscle strength, mobility, and functional independence through progressive exercises targeting specific motor deficits. Virtual reality-based training was also part of this rehabilitation process as an adjunct to conventional rehabilitation to improve dynamic balance and function of the upper and lower limbs, which showed significant improvement in the outcome measures.
PubMed: 38803724
DOI: 10.7759/cureus.59042 -
Pain Research & Management 202430 male patients with primary inguinal hernias undergoing primary inguinal herniorrhaphy were prospectively recruited for ilioinguinal nerve resection and evaluation....
METHODS
30 male patients with primary inguinal hernias undergoing primary inguinal herniorrhaphy were prospectively recruited for ilioinguinal nerve resection and evaluation. Three samples of the resected ilioinguinal nerve (proximal, canal, and distal) were evaluated using Masson's trichrome stain to measure fascicle and total nerve cross-sectional area and detect changes in collagen.
RESULTS
The fascicle cross-sectional area in the canal segment was significantly decreased compared to the proximal control with a large effect size observed ( = 0.016, = 0.16). There was no significant difference in the nerve cross-sectional area between locations, but there was a moderate to large effect size observed between locations ( = 0.165, = 0.105). There was no significant difference in collagen content nor effect size observed between locations ( = 0.99, = 1.503 × 10). . The decrease in the fascicle cross-sectional area within the inguinal canal further suggests that there is chronic pressure applied by hernia tissue consistent with axon degeneration. Collagen content is uniformly distributed along the length of the nerve. Further studies with larger samples are needed to confirm the observed effect of nerve location on the total nerve cross-sectional area and axon loss.
Topics: Humans; Male; Hernia, Inguinal; Middle Aged; Nerve Compression Syndromes; Herniorrhaphy; Inguinal Canal; Aged; Adult; Collagen; Prospective Studies
PubMed: 38803624
DOI: 10.1155/2024/3339753 -
Translational Neurodegeneration May 2024
Topics: Alzheimer Disease; Humans; tau Proteins; Amyloid beta-Peptides; Biomarkers; Neuroglia; Synapses; Nerve Degeneration
PubMed: 38802928
DOI: 10.1186/s40035-024-00420-1 -
Journal of Neuroinflammation May 2024Since the 1990s, evidence has accumulated that macrophages promote peripheral nerve regeneration and are required for enhancing regeneration in the conditioning lesion...
Neither injury induced macrophages within the nerve, nor the environment created by Wallerian degeneration is necessary for enhanced in vivo axon regeneration after peripheral nerve injury.
BACKGROUND
Since the 1990s, evidence has accumulated that macrophages promote peripheral nerve regeneration and are required for enhancing regeneration in the conditioning lesion (CL) response. After a sciatic nerve injury, macrophages accumulate in the injury site, the nerve distal to that site, and the axotomized dorsal root ganglia (DRGs). In the peripheral nervous system, as in other tissues, the macrophage response is derived from both resident macrophages and recruited monocyte-derived macrophages (MDMs). Unresolved questions are: at which sites do macrophages enhance nerve regeneration, and is a particular population needed.
METHODS
Ccr2 knock-out (KO) and Ccr2 knock-in/KO mice were used to prevent MDM recruitment. Using these strains in a sciatic CL paradigm, we examined the necessity of MDMs and residents for CL-enhanced regeneration in vivo and characterized injury-induced nerve inflammation. CL paradigm variants, including the addition of pharmacological macrophage depletion methods, tested the role of various macrophage populations in initiating or sustaining the CL response. In vivo regeneration, measured from bilateral proximal test lesions (TLs) after 2 d, and macrophages were quantified by immunofluorescent staining.
RESULTS
Peripheral CL-enhanced regeneration was equivalent between crush and transection CLs and was sustained for 28 days in both Ccr2 KO and WT mice despite MDM depletion. Similarly, the central CL response measured in dorsal roots was unchanged in Ccr2 KO mice. Macrophages at both the TL and CL, but not between them, stained for the pro-regenerative marker, arginase 1. TL macrophages were primarily CCR2-dependent MDMs and nearly absent in Ccr2 KO and Ccr2 KO mice. However, there were only slightly fewer Arg1 macrophages in CCR2 null CLs than controls due to resident macrophage compensation. Zymosan injection into an intact WT sciatic nerve recruited Arg1 macrophages but did not enhance regeneration. Finally, clodronate injection into Ccr2 KO CLs dramatically reduced CL macrophages. Combined with the Ccr2 KO background, depleting MDMs and TL macrophages, and a transection CL, physically removing the distal nerve environment, nearly all macrophages in the nerve were removed, yet CL-enhanced regeneration was not impaired.
CONCLUSIONS
Macrophages in the sciatic nerve are neither necessary nor sufficient to produce a CL response.
Topics: Animals; Macrophages; Mice; Nerve Regeneration; Wallerian Degeneration; Receptors, CCR2; Peripheral Nerve Injuries; Mice, Inbred C57BL; Mice, Knockout; Sciatic Neuropathy; Axons; Mice, Transgenic; Disease Models, Animal; Sciatic Nerve; Ganglia, Spinal; Green Fluorescent Proteins
PubMed: 38802868
DOI: 10.1186/s12974-024-03132-5 -
BMC Cancer May 2024Cerebellar degeneration-related (CDR) proteins are associated with paraneoplastic cerebellar degeneration (PCD) - a rare, neurodegenerative disease caused by...
BACKGROUND
Cerebellar degeneration-related (CDR) proteins are associated with paraneoplastic cerebellar degeneration (PCD) - a rare, neurodegenerative disease caused by tumour-induced autoimmunity against neural antigens resulting in degeneration of Purkinje neurons in the cerebellum. The pathogenesis of PCD is unknown, in large part due to our limited understanding of the functions of CDR proteins. To this end, we performed an extensive, multi-omics analysis of CDR-knockout cells focusing on the CDR2L protein, to gain a deeper understanding of the properties of the CDR proteins in ovarian cancer.
METHODS
Ovarian cancer cell lines lacking either CDR1, CDR2, or CDR2L were analysed using RNA sequencing and mass spectrometry-based proteomics to assess changes to the transcriptome, proteome and secretome in the absence of these proteins.
RESULTS
For each knockout cell line, we identified sets of differentially expressed genes and proteins. CDR2L-knockout cells displayed a distinct expression profile compared to CDR1- and CDR2-knockout cells. Knockout of CDR2L caused dysregulation of genes involved in ribosome biogenesis, protein translation, and cell cycle progression, ultimately causing impaired cell proliferation in vitro. Several of these genes showed a concurrent upregulation at the transcript level and downregulation at the protein level.
CONCLUSIONS
Our study provides the first integrative multi-omics analysis of the impact of knockout of the CDR genes, providing both new insights into the biological properties of the CDR proteins in ovarian cancer, and a valuable resource for future investigations into the CDR proteins.
Topics: Humans; Cell Proliferation; Ribosomes; Female; Gene Knockout Techniques; Ovarian Neoplasms; Cell Line, Tumor; Proteomics; Nerve Tissue Proteins; Gene Expression Profiling; Transcriptome; Gene Expression Regulation, Neoplastic; Proteome; Multiomics
PubMed: 38802745
DOI: 10.1186/s12885-024-12399-z -
Predictors of Recovery in Facial Nerve Palsy: Insights From an Observational Study in Odisha, India.Cureus Apr 2024Background Facial nerve paralysis, leading to the loss of facial expression, poses significant discomfort to patients. While most individuals exhibit a favorable...
Background Facial nerve paralysis, leading to the loss of facial expression, poses significant discomfort to patients. While most individuals exhibit a favorable response to treatment, a subset experiences enduring facial deformities without clearly defined etiology. This study aimed to identify prognostic factors influencing outcomes and quality of life in facial nerve palsy patients, contributing to enhanced clinical management. Methods A prospective observational study was conducted in the Otorhinolaryngology Department of Maharaja Krishna Chandra Gajapati Medical College and Hospital, a tertiary care hospital. We included patients presenting with any clinical variety of facial nerve palsy, irrespective of age and gender. Only moribund and noncompliant cases were excluded. Patients underwent clinical assessment using the House-Brackmann (HB) grading at presentation and were subsequently monitored at three weeks, three months, and six months post-onset to assess recovery. Results Out of 66 patients, 18 (27.27%) fully recovered at three weeks, 50 (75.76%) recovered at three months, and 54 (81.82%) at six-month follow-up. Incomplete recovery was observed in 13 (19.69%) patients. Factors associated with favorable outcomes included younger age of onset (p = 0.003), lower baseline HB grade (IV or less) (p = 0.001), Electroneurography Degeneration Index (ENoG DI) of <70% (p < 0.0001), early initiation of treatment (within five days of onset) (p = 0.0003), and absence of comorbid conditions (p = 0.03). Gender and affected side (left or right) did not influence the outcome. Conclusion In summary, age, associated comorbid conditions, baseline HB grade, and extent of facial nerve degeneration are crucial predictors of outcomes in facial nerve palsy. This knowledge can guide clinicians in optimizing treatment strategies for improved patient care.
PubMed: 38800142
DOI: 10.7759/cureus.58949