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Neuroscience Mar 2024Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C-terminal...
Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C-terminal fragment of agrin cleaved by neurotrypsin induces dendritic spine formation in the adult hippocampus. Since the α subunit of sodium-potassium ATPase (Na/K ATPase) is a neuronal receptor for agrin in the central nervous system, cardiac glycosides might facilitate dendritic spine formation and subsequent improvements in learning. This study investigated the effects of cardiac glycoside digoxin on dendritic spine turnover and learning performance in mice. Golgi-Cox staining revealed that intraperitoneal injection of digoxin less than its IC in the brain significantly increased the density of long spines (≥2 µm) in the cerebral cortex in wild-type mice and neurotrypsin-knockout (NT-KO) mice showing impairment of activity-dependent spine formation. Although the motor learning performance of NT-KO mice was significantly lower than control wild-type mice under the control condition, low doses of digoxin enhanced performance to a similar degree in both strains. In NT-KO mice, lower digoxin doses equivalent to clinical doses also significantly improved motor learning performance. These data suggest that lower doses of digoxin could modify dendritic spine formation or recycling and facilitate motor learning in compensation for the disruption of neurotrypsin-agrin pathway.
Topics: Mice; Animals; Dendritic Spines; Cardiac Glycosides; Digoxin; Agrin; Mice, Knockout; Adenosine Triphosphatases
PubMed: 38278474
DOI: 10.1016/j.neuroscience.2024.01.018 -
Nutrients Jan 2024Menopause causes a reduction in estradiol (E2) and may be associated with neuromuscular degeneration. Compared to pre-menopausal (PRE-M) women, this study sought to...
Decreased Neuromuscular Function and Muscle Quality along with Increased Systemic Inflammation and Muscle Proteolysis Occurring in the Presence of Decreased Estradiol and Protein Intake in Early to Intermediate Post-Menopausal Women.
Menopause causes a reduction in estradiol (E2) and may be associated with neuromuscular degeneration. Compared to pre-menopausal (PRE-M) women, this study sought to determine dietary protein intake and whether lower levels of circulating E2 in post-menopausal women (POST-M) were occurring alongside increased levels of biomarkers of axonal and neuromuscular junction degeneration (NMJ), inflammation, muscle protein degradation, and reduced indices of muscle quality and performance. Employing a cross-sectional design, PRE-M ( = 6) and POST-M ( = 6) dietary analysis data were collected and participants then donated a blood and urine sample followed by assessments for body composition, motor unit activation, and muscle performance. Independent group -tests were performed to determine differences between groups ( ≤ 0.05). In POST-M women, E2, motor unit activity, muscle quality, and muscle performance were significantly less than those for PRE-M women; however, the levels of -terminal fragment of agrin, tumor necrosis factor-α, and urinary titin were significantly greater ( < 0.05). POST-M women were also shown to be ingesting fewer total calories and less protein than PRE-M ( < 0.05). Reduced E2 and dietary protein intake in POST-M women occurs in conjunction with increased levels of biomarkers of NMJ degradation, inflammation, and muscle proteolysis, which may be associated with reduced motor unit activation and muscle quality.
Topics: Female; Humans; Proteolysis; Cross-Sectional Studies; Dietary Proteins; Postmenopause; Muscles; Biomarkers
PubMed: 38257090
DOI: 10.3390/nu16020197 -
American Journal of Physiology. Cell... Mar 2024This review examined how Hippo cell signaling and heparan sulfate (HS)-proteoglycans (HSPGs) regulate tissue form and function. Despite being a nonweight-bearing tissue,... (Review)
Review
This review examined how Hippo cell signaling and heparan sulfate (HS)-proteoglycans (HSPGs) regulate tissue form and function. Despite being a nonweight-bearing tissue, the brain is regulated by Hippo mechanoresponsive cell signaling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens, and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes shut (Eys) interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense. Another HSPG, Neurexin interacts with structural and adaptor proteins to stabilize synapses and ensure specificity of neural interactions, and aids in synaptic potentiation and plasticity in neurotransduction. HSPGs also stabilize the blood-brain barrier and motor neuron basal structures in the neuromuscular junction. Agrin and perlecan localize acetylcholinesterase and its receptors in the neuromuscular junction essential for neuromuscular control. The primary cilium is a mechanosensory hub on neurons, utilized by YES associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) Hippo, Hh, Wnt, transforming growth factor (TGF)-β/bone matrix protein (BMP) receptor tyrosine kinase cell signaling. Members of the glypican HSPG proteoglycan family interact with Smoothened and Patched G-protein coupled receptors on the cilium to regulate Hh and Wnt signaling during neuronal development. Control of glycosyl sulfotransferases and endogenous protease expression by Hippo TAZ YAP represents a mechanism whereby the fine structure of HS-proteoglycans can be potentially modulated spatiotemporally to regulate tissue morphogenesis in a similar manner to how Hippo signaling controls sialyltransferase expression and mediation of cell-cell recognition, dysfunctional sialic acid expression is a feature of many tumors.
Topics: Female; Pregnancy; Humans; Heparan Sulfate Proteoglycans; Hippo Signaling Pathway; Acetylcholinesterase; Extracellular Matrix; Extracellular Matrix Proteins; Wnt Signaling Pathway; Receptor Protein-Tyrosine Kinases
PubMed: 38223931
DOI: 10.1152/ajpcell.00683.2023 -
Cell Death & Disease Jan 2024The tumor microenvironment is a complex ecosystem that plays a critical role in cancer progression and treatment response. Recently, extracellular amyloid fibrils have...
The tumor microenvironment is a complex ecosystem that plays a critical role in cancer progression and treatment response. Recently, extracellular amyloid fibrils have emerged as novel components of the tumor microenvironment; however, their function remains elusive. In this study, we establish a direct connection between the presence of amyloid fibrils in the secretome and the activation of YAP, a transcriptional co-activator involved in cancer proliferation and drug resistance. Furthermore, we uncover a shared mechano-signaling mechanism triggered by amyloid fibrils in both melanoma and pancreatic ductal adenocarcinoma cells. Our findings highlight the crucial role of the glycocalyx protein Agrin which binds to extracellular amyloid fibrils and acts as a necessary factor in driving amyloid-dependent YAP activation. Additionally, we reveal the involvement of the HIPPO pathway core kinase LATS1 in this signaling cascade. Finally, we demonstrate that extracellular amyloid fibrils enhance cancer cell migration and invasion. In conclusion, our research expands our knowledge of the tumor microenvironment by uncovering the role of extracellular amyloid fibrils in driving mechano-signaling and YAP activation. This knowledge opens up new avenues for developing innovative strategies to modulate YAP activation and mitigate its detrimental effects during cancer progression.
Topics: Humans; Amyloid; Ecosystem; Signal Transduction; Melanoma; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 38199984
DOI: 10.1038/s41419-024-06424-z -
Cell Reports Jan 2024Perlecan (HSPG2), a heparan sulfate proteoglycan similar to agrin, is key for extracellular matrix (ECM) maturation and stabilization. Although crucial for cardiac...
Perlecan (HSPG2), a heparan sulfate proteoglycan similar to agrin, is key for extracellular matrix (ECM) maturation and stabilization. Although crucial for cardiac development, its role remains elusive. We show that perlecan expression increases as cardiomyocytes mature in vivo and during human pluripotent stem cell differentiation to cardiomyocytes (hPSC-CMs). Perlecan-haploinsuffient hPSCs (HSPG2) differentiate efficiently, but late-stage CMs have structural, contractile, metabolic, and ECM gene dysregulation. In keeping with this, late-stage HSPG2 hPSC-CMs have immature features, including reduced ⍺-actinin expression and increased glycolytic metabolism and proliferation. Moreover, perlecan-haploinsuffient engineered heart tissues have reduced tissue thickness and force generation. Conversely, hPSC-CMs grown on a perlecan-peptide substrate are enlarged and display increased nucleation, typical of hypertrophic growth. Together, perlecan appears to play the opposite role of agrin, promoting cellular maturation rather than hyperplasia and proliferation. Perlecan signaling is likely mediated via its binding to the dystroglycan complex. Targeting perlecan-dependent signaling may help reverse the phenotypic switch common to heart failure.
Topics: Humans; Heparan Sulfate Proteoglycans; Agrin; Myocytes, Cardiac; Extracellular Matrix; Extracellular Matrix Proteins
PubMed: 38198277
DOI: 10.1016/j.celrep.2023.113668 -
BioRxiv : the Preprint Server For... Dec 2023Matriglycan (-1,3-β-glucuronic acid-1,3-α-xylose-) is a polysaccharide that is synthesized on α-dystroglycan, where it functions as a high-affinity glycan receptor...
Matriglycan (-1,3-β-glucuronic acid-1,3-α-xylose-) is a polysaccharide that is synthesized on α-dystroglycan, where it functions as a high-affinity glycan receptor for extracellular proteins, such as laminin, perlecan and agrin, thus anchoring the plasma membrane to the extracellular matrix. This biological activity is closely associated with the size of matriglycan. Using high-resolution mass spectrometry and site-specific mutant mice, we show for the first time that matriglycan on the T317/T319 and T379 sites of α-dystroglycan are not identical. T379-linked matriglycan is shorter than the previously characterized T317/T319-linked matriglycan, although it maintains its laminin binding capacity. Transgenic mice with only the shorter T379-linked matriglycan exhibited mild embryonic lethality, but those that survived were healthy. The shorter T379-linked matriglycan exists in multiple tissues and maintains neuromuscular function in adult mice. In addition, the genetic transfer of α-dystroglycan carrying just the short matriglycan restored grip strength and protected skeletal muscle from eccentric contraction-induced damage in muscle-specific dystroglycan knock-out mice. Due to the effects that matriglycan imparts on the extracellular proteome and its ability to modulate cell-matrix interactions, our work suggests that differential regulation of matriglycan length in various tissues optimizes the extracellular environment for unique cell types.
PubMed: 38187633
DOI: 10.1101/2023.12.20.572361 -
Molecular Neurobiology Dec 2023Motopsin, a serine protease encoded by PRSS12, is secreted by neuronal cells into the synaptic clefts in an activity-dependent manner, where it induces synaptogenesis by...
Overexpression of Motopsin, an Extracellular Serine Protease Related to Intellectual Disability, Promotes Adult Neurogenesis and Neuronal Responsiveness in the Dentate Gyrus.
Motopsin, a serine protease encoded by PRSS12, is secreted by neuronal cells into the synaptic clefts in an activity-dependent manner, where it induces synaptogenesis by modulating Na/K-ATPase activity. In humans, motopsin deficiency leads to severe intellectual disability and, in mice, it disturbs spatial memory and social behavior. In this study, we investigated mice that overexpressed motopsin in the forebrain using the Tet-Off system (DTG-OE mice). The elevated agrin cleavage or the reduced Na/K-ATPase activity was not detected. However, motopsin overexpression led to a reduction in spine density in hippocampal CA1 basal dendrites. While motopsin overexpression decreased the ratio of mature mushroom spines in the DG, it increased the ratio of immature thin spines in CA1 apical dendrites. Female DTG-OE mice showed elevated locomotor activity in their home cages. DTG-OE mice showed aberrant behaviors, such as delayed latency to the target hole in the Barnes maze test and prolonged duration of sniffing objects in the novel object recognition test (NOR), although they retained memory comparable to that of TRE-motopsin littermates, which normally express motopsin. After NOR, c-Fos-positive cells increased in the dentate gyrus (DG) of DTG-OE mice compared with that of DTG-SO littermates, in which motopsin overexpression was suppressed by the administration of doxycycline, and TRE-motopsin littermates. Notably, the numbers of doublecortin- and 5-bromo-2'-deoxyuridine-labeled cells significantly increased in the DG of DTG-OE mice, suggesting increased adult neurogenesis. Importantly, our results revealed a new function in addition to modulating neuronal responsiveness and spine morphology in the DG: the regulation of neurogenesis.
PubMed: 38153682
DOI: 10.1007/s12035-023-03890-y -
European Journal of Medical Genetics Feb 2024LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate... (Review)
Review
LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third β-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).
Topics: Female; Humans; Infant, Newborn; Hyperostosis; LDL-Receptor Related Proteins; Myasthenic Syndromes, Congenital; Neuromuscular Junction; Syndactyly; Male
PubMed: 38101565
DOI: 10.1016/j.ejmg.2023.104903 -
ACS Nano Dec 2023Spinal cord injury (SCI) causes tissue structure damage and composition changes of the neural parenchyma, resulting in severe consequences for spinal cord function....
Spinal cord injury (SCI) causes tissue structure damage and composition changes of the neural parenchyma, resulting in severe consequences for spinal cord function. Mimicking the components and microstructure of spinal cord tissues holds promise for restoring the regenerative microenvironment after SCI. Here, we have utilized electrospinning technology to develop aligned decellularized spinal cord fibers (A-DSCF) without requiring synthetic polymers or organic solvents. A-DSCF preserves multiple types of spinal cord extracellular matrix proteins and forms a parallel-oriented structure. Compared to aligned collagen fibers (A-CF), A-DSCF exhibits stronger mechanical properties, improved enzymatic stability, and superior functionality in the adhesion, proliferation, axonal extension, and myelination of differentiated neural progenitor cells (NPCs). Notably, axon extension or myelination has been primarily linked to Agrin (AGRN), Laminin (LN), or Collagen type IV (COL IV) proteins in A-DSCF. When transplanted into rats with complete SCI, A-DSCF loaded with NPCs improves the survival, maturation, axon regeneration, and motor function of the SCI rats. These findings highlight the potential of structurally and compositionally biomimetic scaffolds to promote axonal extension and remyelination after SCI.
Topics: Rats; Animals; Axons; Remyelination; Nerve Regeneration; Spinal Cord; Spinal Cord Injuries
PubMed: 38078771
DOI: 10.1021/acsnano.3c09892 -
Brain Research Feb 2024The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous... (Review)
Review
The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.
Topics: LDL-Receptor Related Proteins; Agrin; Amyloid beta-Peptides; Receptor Protein-Tyrosine Kinases; Neuromuscular Junction
PubMed: 38065285
DOI: 10.1016/j.brainres.2023.148705