scholarly journals Motor nuclei innervating eye muscles spared in mouse model of SOD1-linked ALS

2018 ◽  
Author(s):  
Eleanor V. Thomas ◽  
Maria Nagy ◽  
Hongyu Zhao ◽  
Wayne A. Fenton ◽  
Arthur L. Horwich
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Mouse Strain ◽  
Cranial Nerve ◽  
Motor System ◽  
Eye Muscles ◽  
Progressive Loss ◽  
Motor Nuclei ◽  
End Stage ◽  
Human Sod1

SummaryThe eye muscles of humans with either inherited or sporadic forms of ALS are relatively unaffected during disease progression, a function of sparing of the cranial nerve motor neurons supplying them. Here we observe that cranial nerve nuclei are also spared in a mouse model of inherited SOD1-linked ALS. We examined the cranial nerve motor nuclei in a mouse strain, G85R SOD1YFP, which carries a high copy transgene encoding a mutant human SOD1-YFP fusion protein, that exhibits florid YFP-fluorescent aggregates in spinal cord motor neurons and paralyzes by 6 months of age. We observed in the cranial nerve nuclei that innervate the eye, 3N (oculomotor), 4N (trochlear), and 6N (abducens), that there was little (4N, 6N) or no (3N) aggregation, in comparison with other motor nuclei, 5N (trigeminal), 7N (facial), and 12N (hypoglossal), in the latter two of which florid aggregation was observed. Correspondingly, the number of ChAT positive motor neurons in 3N of G85R SOD1YFP relative to that in 3N of ChAT-EGFP mice showed that there was no loss of motor neurons over time, whereas in 12N there was progressive loss of motor neurons, amounting to a loss of ∼30% from G85R SOD1YFP by end-stage. Thus, the sparing of extraocular motor neurons as occurs in humans with ALS appears to be replicated in our SOD1-linked ALS mouse strain, supporting the validity of the mouse model for studying this aspect of selective motor system loss in ALS. Comparisons of extraocular motor neurons (e.g., from 3N), resistant to ALS pathology, with other cranial motor neurons (e.g., from 12N), sensitive to such pathology, may thus be of value in understanding mechanisms of protection vs. susceptibility of motor neurons.

scholarly journals Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

2021 ◽  
Author(s):  
Phan H. Truong ◽  
Peter J. Crouch ◽  
James B. W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

AbstractMotor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

scholarly journals Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

2019 ◽  
Author(s):  
Christine Marques ◽  
Mathieu Fischer ◽  
Céline Keime ◽  
Thibaut Burg ◽  
Aurore Brunet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Rna Metabolism ◽  
Initiation Site ◽  
Spinal Motor Neurons ◽  
Adult Mice ◽  
End Stage ◽  
Neuronal Functions ◽  
Potential Initiation

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.

scholarly journals Sex Dependent Effects of Amyloid Precursor-Like Protein 2 in The SOD1-G37R Transgenic Mouse Model of MND.

2021 ◽  
Author(s):  
Phan Hong Truong ◽  
Peter J. Crouch ◽  
James B.W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

Abstract Introduction: Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. Methods In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. Results We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the end-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2-/- mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. Conclusion These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP-family as a potential target for further investigation into the cause and regulation of MND.

scholarly journals Inhibition of Kirsten-Ras reduces fibrosis and protects against renal dysfunction in a mouse model of chronic folic acid nephropathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lucy J. Newbury ◽  
Jui-Hui Wang ◽  
Gene Hung ◽  
Bruce M. Hendry ◽  
Claire C. Sharpe
Keyword(s):  
Folic Acid ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Dysfunction ◽  
Antisense Oligonucleotides ◽  
Underlying Mechanism ◽  
Therapeutic Benefit ◽  
End Stage

Abstract Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated in vitro and in vivo that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.

scholarly journals Catecholaminergic Fiber Innervation of the Vocal Motor System Is Intrasexually Dimorphic in a Teleost with Alternative Reproductive Tactics

2015 ◽  
Vol 86 (2) ◽  
pp. 131-144 ◽  
Author(s):  
Zachary N. Ghahramani ◽  
Miky Timothy ◽  
Gurpreet Kaur ◽  
Michelle Gorbonosov ◽  
Alena Chernenko ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Motor System ◽  
Advertisement Call ◽  
Motor Nucleus ◽  
Type I ◽  
Type Ii ◽  
Fiber Density ◽  
Reproductive Tactics ◽  
Long Duration ◽  
Behavioral Divergence

Catecholamines, which include the neurotransmitters dopamine and noradrenaline, are known modulators of sensorimotor function, reproduction, and sexually motivated behaviors across vertebrates, including vocal-acoustic communication. Recently, we demonstrated robust catecholaminergic (CA) innervation throughout the vocal motor system in the plainfin midshipman fish Porichthys notatus, a seasonal breeding marine teleost that produces vocal signals for social communication. There are 2 distinct male reproductive morphs in this species: type I males establish nests and court females with a long-duration advertisement call, while type II males sneak spawn to steal fertilizations from type I males. Like females, type II males can only produce brief, agonistic, grunt type vocalizations. Here, we tested the hypothesis that intrasexual differences in the number of CA neurons and their fiber innervation patterns throughout the vocal motor pathway may provide neural substrates underlying divergence in reproductive behavior between morphs. We employed immunofluorescence (-ir) histochemistry to measure tyrosine hydroxylase (TH; a rate-limiting enzyme in catecholamine synthesis) neuron numbers in several forebrain and hindbrain nuclei as well as TH-ir fiber innervation throughout the vocal pathway in type I and type II males collected from nests during the summer reproductive season. After controlling for differences in body size, only one group of CA neurons displayed an unequivocal difference between male morphs: the extraventricular vagal-associated TH-ir neurons, located just lateral to the dimorphic vocal motor nucleus (VMN), were significantly greater in number in type II males. In addition, type II males exhibited greater TH-ir fiber density within the VMN and greater numbers of TH-ir varicosities with putative contacts on vocal motor neurons. This strong inverse relationship between the predominant vocal morphotype and the CA innervation of vocal motor neurons suggests that catecholamines may function to inhibit vocal output in midshipman. These findings support catecholamines as direct modulators of vocal behavior, and differential CA input appears reflective of social and reproductive behavioral divergence between male midshipman morphs.

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
Author(s):  
Kumar Sharma ◽  
Peter McCue ◽  
Stephen R. Dunn
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Disease ◽  
Mouse Models ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Matrix Expansion ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

The vestibuloocular reflex of the adult flatfish. I. Oculomotor organization

1985 ◽  
Vol 54 (4) ◽  
pp. 887-899 ◽  
Author(s):  
W. Graf ◽  
R. Baker
Keyword(s):  
Eye Movements ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Vertical Plane ◽  
Extraocular Muscles ◽  
The Body ◽  
Medial Rectus ◽  
Inferior Rectus ◽  
Abducens Nucleus ◽  
Eye Muscles

The flatfish species constitute a natural paradigm for investigating adaptive changes in the vertebrate central nervous system. During metamorphosis all species of flatfish experience a 90 degree change in orientation between their vestibular and extraocular coordinate axes. As a result, the optic axes of both eyes maintain their orientation with respect to earth horizontal, but the horizontal semicircular canals become oriented vertically. Since the flatfish propels its body with the same swimming movements when referenced to the body as a normal fish, the horizontal canals are exposed to identical accelerations, but in the flatfish these accelerations occur in a vertical plane. The appropriate compensatory eye movements are simultaneous rotations of both eyes forward or backward (i.e., parallel), in contrast to the symmetric eye movements in upright fish (i.e., one eye moves forward, the other backward). Therefore, changes in the extraocular muscle arrangement and/or the neuronal connectivity are required. This study describes the peripheral and central oculomotor organization in the adult winter flounder, Pseudopleuronectes americanus. At the level of the peripheral oculomotor apparatus, the sizes of the horizontal extraocular muscles (lateral and medial rectus) were considerably smaller than those of the vertical eye muscles, as quantified by fiber counts and area measurements of cross sections of individual muscles. However, the spatial orientations and the kinematic characteristics of all six extraocular muscles were not different from those described in comparable lateral-eyed animals. There were no detectable asymmetries between the left and the right eye. Central oculomotor organization was investigated by extracellular horseradish peroxidase injections into individual eye muscles. Commonly described distributions of extraocular motor neurons in the oculomotor, trochlear, and abducens nuclei were found. These motor neuron pools consisted of two contralateral (superior rectus and superior oblique) and four ipsilateral populations (inferior oblique, inferior rectus, medial rectus, and lateral rectus). The labeled cells formed distinct motor neuron populations, which overlapped little. As expected, the numbers of labeled motoneurons differed in horizontal and vertical eye movers. The numerical difference was especially prominent in comparing the abducens nucleus with one of the vertical recti subdivisions. Nevertheless, there was bilateral symmetry between the motoneurons projecting to the left and right eyes.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3060
Author(s):  
Shin-Ruen Yang ◽  
Szu-Chun Hung ◽  
Lichieh Julie Chu ◽  
Kuo-Feng Hua ◽  
Chyou-Wei Wei ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Renal Tissue ◽  
Drug Candidate ◽  
Therapeutic Effects ◽  
Tubulointerstitial Lesions ◽  
Cytokine Levels ◽  
Renal Tubular ◽  
Stage Renal Disease ◽  
End Stage

Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC50, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.

scholarly journals Selective disruption of trigeminal sensory neurogenesis and differentiation in a mouse model of 22q11.2 deletion syndrome

2021 ◽  
pp. dmm.047357
Author(s):  
Beverly A. Karpinski ◽  
Thomas M. Maynard ◽  
Corey A. Bryan ◽  
Gelila Yitsege ◽  
Anelia Horvath ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neural Crest ◽  
Sensory Neuron ◽  
Cranial Nerve ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Neuron Differentiation ◽  
Pediatric Dysphagia ◽  
Cell Cell

22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we asked whether sensory neuron differentiation in the trigeminal ganglion (CNgV) , which is essential for normal orofacial function, is disrupted. We did not detect changes in cranial placode cell translocation or neural crest migration at early stages of LgDel CNgV development. As the ganglion coalesces, however, proportions of placode-derived LgDel CNgV cells increase relative to neural crest cells. In addition, local aggregation of placode-derived cells increases and aggregation of neural crest-derived cells decreases in LgDel CNgV. This change in cell-cell relationships was accompanied by altered proliferation of placode-derived cells at E9.5, and premature neurogenesis from neural crest-derived precursors, reflected by increased frequency of asymmetric neurogenic divisions for neural crest-derived precursors by E10.5. These early differences in LgDel CNgV genesis prefigure changes in sensory neuron differentiation and gene expression by P8, when early signs of cranial nerve dysfunction associated with pediatric dysphagia are observed in LgDel mice. Apparently, 22q11 deletion destabilizes CNgV sensory neuron genesis and differentiation by increasing variability in cell-cell interaction, proliferation, and sensory neuron differentiation. This early developmental divergence and its consequences may contribute to oropharyngeal dysfunction including suckling, feeding and swallowing disruptions at birth and additional orofacial sensory/motor deficits throughout life.

scholarly journals Periodontal Disease in Patients Receiving Dialysis

2019 ◽  
Vol 20 (15) ◽  
pp. 3805
Author(s):  
Yasuyoshi Miyata ◽  
Yoko Obata ◽  
Yasushi Mochizuki ◽  
Mineaki Kitamura ◽  
Kensuke Mitsunari ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Periodontal Disease ◽  
Replacement Therapy ◽  
Healthy Individuals ◽  
Progressive Loss ◽  
Medical Instruments ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Impact

Chronic kidney disease (CKD) is characterized by kidney damage with proteinuria, hematuria, and progressive loss of kidney function. The final stage of CKD is known as end-stage renal disease, which usually indicates that approximately 90% of normal renal function is lost, and necessitates renal replacement therapy for survival. The most widespread renal replacement therapy is dialysis, which includes peritoneal dialysis (PD) and hemodialysis (HD). However, despite the development of novel medical instruments and agents, both dialysis procedures have complications and disadvantages, such as cardiovascular disease due to excessive blood fluid and infections caused by impaired immunity. Periodontal disease is chronic inflammation induced by various pathogens and its frequency and severity in patients undergoing dialysis are higher compared to those in healthy individuals. Therefore, several investigators have paid special attention to the impact of periodontal disease on inflammation-, nutrient-, and bone metabolism-related markers; the immune system; and complications in patients undergoing dialysis. Furthermore, the influence of diabetes on the prevalence and severity of manifestations of periodontal disease, and the properties of saliva in HD patients with periodontitis have been reported. Conversely, there are few reviews discussing periodontal disease in patients with dialysis. In this review, we discuss the available studies and review the pathological roles and clinical significance of periodontal disease in patients receiving PD or HD. In addition, this review underlines the importance of oral health and adequate periodontal treatment to maintain quality of life and prolong survival in these patients.

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