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 Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

scholarly journals Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sebastian Poliak ◽  
Daniel Morales ◽  
Louis-Philippe Croteau ◽  
Dayana Krawchuk ◽  
Elena Palmesino ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Growth Cones ◽  
In Vitro Assays ◽  
Dependent Manner ◽  
Motor Axons ◽  
Spinal Motor Neurons ◽  
Spinal Motor

During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin–ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways.

Impaired hypoxic sensor Siah-1, PHD3, and FIH system in spinal motor neurons of an amyotrophic lateral sclerosis mouse model

2012 ◽  
Vol 91 (2) ◽  
pp. 285-291
Author(s):  
Kota Sato ◽  
Nobutoshi Morimoto ◽  
Tomoko Kurata ◽  
Takafumi Mimoto ◽  
Kazunori Miyazaki ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Lateral Sclerosis

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 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.

Abnormal RNA metabolism in spinal motor neurons in the wobbler mouse

1981 ◽  
Vol 4 (5) ◽  
pp. 407-412 ◽  
Author(s):  
T. Murakami ◽  
F. L. Mastaglia ◽  
D. M. A. Mann ◽  
W. G. Bradley
Keyword(s):  
Motor Neurons ◽  
Rna Metabolism ◽  
Wobbler Mouse ◽  
Spinal Motor Neurons ◽  
Spinal Motor

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.

AIF translocates to the nucleus in the spinal motor neurons in a mouse model of ALS

2006 ◽  
Vol 406 (3) ◽  
pp. 205-210 ◽  
Author(s):  
Yeo Kyoung Oh ◽  
Ki Soon Shin ◽  
Shin Jung Kang
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Spinal Motor
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