scholarly journals Experimental Motor Neuron Disease Induced in Mice with Long-Term Repeated Intraperitoneal Injections of Serum from ALS Patients

2019 ◽  
Vol 20 (10) ◽  
pp. 2573 ◽  
Author(s):  
Izabella Obál ◽  
Bernát Nógrádi ◽  
Valéria Meszlényi ◽  
Roland Patai ◽  
Gerda Ricken ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Intracellular Calcium ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Isometric Force ◽  
Motor Nerve ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Gradual Loss ◽  
Als Patients

In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons was noted, to test whether the ALS IgG in this paradigm has the potential to evoke relentless degeneration of motor neurons, treatment with repeated injections over a longer period was carried out. Mice were systematically injected intraperitoneally with serum taken from ALS patients over a 75-day period. At selected time points, the isometric force of the limbs, number of spinal motor neurons and their intracellular calcium levels were determined. Furthermore, markers of glial activation and the motoneuronal uptake of human IgG were monitored. During this period, gliosis and progressive motoneuronal degeneration developed, which led to gradual loss of spinal motor neurons, more than 40% at day 21, along with decreasing muscle strength in the limbs. The inclusion-like accumulation of IgG appeared in the perikarya with the increase of intracellular calcium in the cell bodies and motor nerve terminals. Our results demonstrate that ALS serum can transfer motor neuron disease to mice.

scholarly journals Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Alison M. Hixon ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Sialic Acid ◽  
Motor Neuron ◽  
Axonal Transport ◽  
Motor Neurons ◽  
The United States ◽  
Retrograde Axonal Transport ◽  
Spinal Motor Neurons ◽  
Acute Flaccid Myelitis ◽  
Spinal Motor ◽  
Enterovirus D68

ABSTRACTEnterovirus D68 (EV-D68) is an emerging virus that has been identified as a cause of recent outbreaks of acute flaccid myelitis (AFM), a poliomyelitis-like spinal cord syndrome that can result in permanent paralysis and disability. In experimental mouse models, EV-D68 spreads to, infects, and kills spinal motor neurons following infection by various routes of inoculation. The topography of virus-induced motor neuron loss correlates with the pattern of paralysis. The mechanism(s) by which EV-D68 spreads to target motor neurons remains unclear. We sought to determine the capacity of EV-D68 to spread by the neuronal route and to determine the role of known EV-D68 receptors, sialic acid and intracellular adhesion molecule 5 (ICAM-5), in neuronal infection. To do this, we utilized a microfluidic chamber culture system in which human induced pluripotent stem cell (iPSC) motor neuron cell bodies and axons can be compartmentalized for independent experimental manipulation. We found that EV-D68 can infect motor neurons via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies. Virus was not released from the axons via anterograde axonal transport after infection of the cell bodies. Prototypic strains of EV-D68 depended on sialic acid for axonal infection and transport, while contemporary circulating strains isolated during the 2014 EV-D68 outbreak did not. The pattern of infection did not correspond with the ICAM-5 distribution and expression in either human tissue, the mouse model, or the iPSC motor neurons.IMPORTANCEEnterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.

Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology

2008 ◽  
Vol 29 (3) ◽  
pp. 400-408 ◽  
Author(s):  
Lijun Wang ◽  
Kamal Sharma ◽  
Han-Xiang Deng ◽  
Teepu Siddique ◽  
Gabriella Grisotti ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Mutant Sod1 ◽  
Spinal Motor Neurons ◽  
Spinal Motor

scholarly journals Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

2019 ◽  
Vol 116 (10) ◽  
pp. 4696-4705 ◽  
Author(s):  
Joy Mitra ◽  
Erika N. Guerrero ◽  
Pavana M. Hegde ◽  
Nicole F. Liachko ◽  
Haibo Wang ◽  
...  
Keyword(s):  
Dna Binding ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Strand Break ◽  
Double Strand Break ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Sporadic Als ◽  
Als Patients

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and inCaenorhabditis elegansmutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

scholarly journals SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Alison L. Hogan ◽  
Natalie Grima ◽  
Jennifer A. Fifita ◽  
Emily P. McCann ◽  
Benjamin Heng ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Motor Neurons ◽  
Splicing Factor ◽  
Pathological Feature ◽  
Central Nervous System Tissue ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Als Patients ◽  
And Control ◽  
Lateral Sclerosis

AbstractBackgroundSplicing factor proline and glutamine rich (SFPQ, also known as polypyrimidine tract-binding protein-associated-splicing factor, PSF) is a RNA-DNA binding protein with roles in key cellular pathways such as DNA transcription and repair, RNA processing and paraspeckle formation. Dysregulation of SFPQ is emerging as a common pathological feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Increased retention of SFPQ intron nine and nuclear loss of the protein have been linked to multiple genetic subtypes of ALS. Consequently, SFPQ dysregulation has been hypothesised to be a common pathological feature of this highly heterogeneous disease.MethodsThis study provides a comprehensive assessment of SFPQ pathology in large ALS patient cohorts. SFPQ gene expression and intron nine retention were examined in multiple neuroanatomical regions and blood from ALS patients and control individuals using RNA sequencing (RNA-Seq) and quantitative PCR (RT-qPCR). SFPQ protein levels were assessed by immunoblotting of patient and control motor cortex and SFPQ expression pattern was examined by immunofluorescent staining of patient and control spinal cord sections. Finally, whole-genome sequencing data from a large cohort of sporadic ALS patients was analysed for genetic variation in SFPQ.ResultsSFPQ intron nine retention was significantly increased in ALS patient motor cortex. Total SFPQ mRNA expression was significantly downregulated in ALS patient motor cortex but not ALS patient blood, indicating tissue specific SFPQ dysregulation. At the protein level, nuclear expression of SFPQ in both control and patient spinal motor neurons was highly variable and nuclear depletion of SFPQ was not a consistent feature in our ALS cohort. However, we did observe SFPQ-positive cytoplasmic ubiquitinated protein aggregates in ALS spinal motor neurons. In addition, our genetic screen of ALS patients identified two novel, and two rare sequence variants in SFPQ not previously reported in ALS.ConclusionsThis study shows that dysregulation of SFPQ is a feature of ALS patient central nervous system tissue. These findings confirm SFPQ pathology as a feature of ALS and indicate that investigations into the functional consequences of this pathology will provide insight into the biology of ALS.

Developmental regulation of the orphan receptor COUP-TF II gene in spinal motor neurons

Development ◽  
1994 ◽  
Vol 120 (1) ◽  
pp. 25-36 ◽  
Author(s):  
B. Lutz ◽  
S. Kuratani ◽  
A.J. Cooney ◽  
S. Wawersik ◽  
S.Y. Tsai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Thyroid Hormone ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Northern Analysis ◽  
Spinal Motor Neurons ◽  
Spinal Motor

Members of the steroid/thyroid hormone receptor superfamily are involved in the control of cell identity and of pattern formation during embryonic development. Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) can act as regulators of various steroid/thyroid hormone receptor pathways. To begin to study the role of COUP-TFs during embryogenesis, we cloned a chicken COUP-TF (cCOUP-TF II) which is highly homologous to human COUP-TF II. Northern analysis revealed high levels of cCOUP-TF II transcripts during organogenesis. Nuclear extracts from whole embryos and from embryonic spinal cords were used in electrophoretic mobility shift assays. These assays showed that COUP-TF protein is present in these tissues and is capable of binding to a COUP element (a direct repeat of AGGTCA with one base pair spacing). Analysis of cCOUP-TF expression by in situ hybridization revealed high levels of cCOUP-TF II mRNA in the developing spinal motor neurons. Since the ventral properties of the spinal cord, including the development of motor neurons, is in part established by inductive signals from the notochord, we transplanted an additional notochord next to the dorsal region of the neural tube in order to induce ectopic motor neurons. We observed that an ectopic notochord induced cCOUP-TF II gene expression in the dorsal spinal cord in a region coextensive with ectopic domains of SC1 and Islet-1, two previously identified motor neuron markers. Collectively, our studies raise the possibility that cCOUP-TF II is involved in motor neuron development.

The zebrafish detour gene is essential for cranial but not spinal motor neuron induction

Development ◽  
1999 ◽  
Vol 126 (12) ◽  
pp. 2727-2737 ◽  
Author(s):  
A. Chandrasekhar ◽  
H.E. Schauerte ◽  
P. Haffter ◽  
J.Y. Kuwada
Keyword(s):  
Spinal Cord ◽  
Cell Death ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Spinal Motor Neuron ◽  
Neuronal Phenotype ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Hh Signaling ◽  
Function Cell

The zebrafish detour (dtr) mutation generates a novel neuronal phenotype. In dtr mutants, most cranial motor neurons, especially the branchiomotor, are missing. However, spinal motor neurons are generated normally. The loss of cranial motor neurons is not due to aberrant hindbrain patterning, failure of neurogenesis, increased cell death or absence of hh expression. Furthermore, activation of the Hh pathway, which normally induces branchiomotor neurons, fails to induce motor neurons in the dtr hindbrain. Despite this, not all Hh-mediated regulation of hindbrain development is abolished since the regulation of a neural gene by Hh is intact in the dtr hindbrain. Finally, dtr can function cell autonomously to induce branchiomotor neurons. These results suggest that detour encodes a component of the Hh signaling pathway that is essential for the induction of motor neurons in the hindbrain but not in the spinal cord and that dtr function is required for the induction of only a subset of Hh-mediated events in the hindbrain.

scholarly journals Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

2016 ◽  
Vol 113 (47) ◽  
pp. E7580-E7589 ◽  
Author(s):  
Nhat T. T. Le ◽  
Lydia Chang ◽  
Irina Kovlyagina ◽  
Polymnia Georgiou ◽  
Nathaniel Safren ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Hippocampal Neurons ◽  
Missense Mutations ◽  
Spinal Motor Neurons ◽  
Stage Disease ◽  
End Stage ◽  
Brain And Spinal Cord ◽  
The Brain

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS–FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS–FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS–FTD pathogenesis and for investigating therapeutic strategies to halt disease.

scholarly journals Identification of 17 highly expressed genes within mouse lumbar spinal cord anterior horn region from an in-situ hybridization atlas of 3430 genes: implications for motor neuron disease

2014 ◽  
Vol 6 (2) ◽  
Author(s):  
Michael A. Meyer
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Janus Kinase ◽  
Anterior Horn ◽  
Lumbar Spinal Cord ◽  
Spinal Motor ◽  
Lumbar Spinal

In an effort to find possible new gene candidates involved in the causation of amyotrophic lateral sclerosis (ALS), a prior version of the on-line brain gene expression atlas GENSAT was extensively searched for selectively intense expression within spinal motor neurons. Using autoradiographic data of <em>in</em>-<em>situ</em> hybridization from 3430 genes, a search for selectively intense activity was made for the anterior horn region of murine lumbar spinal cord sectioned in the axial plane. Of 3430 genes, a group of 17 genes was found to be highly expressed within the anterior horn suggesting localization to its primary cellular constituent, the alpha spinal motor neuron. For some genes, an inter-relationship to ALS was already known, such as for heavy, medium, and light neurofilaments, and peripherin. Other genes identified include: <em>Gamma Synuclein, GDNF, SEMA3A, Extended Synaptotagmin-like protein 1, LYNX1, HSPA12a, Cadherin 22, PRKACA, TPPP3</em> as well as <em>Choline Acetyltransferase, Janus Kinase 1</em>, and the<em> Motor Neuron</em> and <em>Pancreas Homeobox 1</em>. Based on this study, <em>Fibroblast Growth Factor 1</em> was found to have a particularly selective and intense localization pattern to the ventral horn and may be a good target for development of motor neuron disease therapies; further research is needed.

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