scholarly journals Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (3) ◽  
pp. 369
Author(s):  
Christine Marques ◽  
Thibaut Burg ◽  
Jelena Scekic-Zahirovic ◽  
Mathieu Fischer ◽  
Caroline Rouaux
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Lumbar Spinal Cord ◽  
Retrograde Labelling ◽  
Neuronal Populations ◽  
Temporal Relationships ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: (i) are the degenerations of these two neuronal populations somatotopically related? and if yes (ii), where does neurodegeneration start? If studies carried out on ALS patients clearly demonstrated the somatotopic relationship between UMN and LMN degenerations, their temporal relationship remained an unanswered question. In the present study, we took advantage of the well-described Sod1G86R model of ALS to interrogate the somatotopic and temporal relationships between UMN and LMN degenerations in ALS. Using retrograde labelling from the cervical or lumbar spinal cord of Sod1G86R mice and controls to identify UMN, along with electrophysiology and histology to assess LMN degeneration, we applied rigorous sampling, counting, and statistical analyses, and show that UMN and LMN degenerations are somatotopically related and that UMN depletion precedes LMN degeneration. Together, the data indicate that UMN degeneration is a particularly early and thus relevant event in ALS, in accordance with a possible cortical origin of the disease, and emphasize the need to further elucidate the molecular mechanisms behind UMN degeneration, towards new therapeutic avenues.

scholarly journals Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

2021 ◽  
Author(s):  
Jack Humphrey ◽  
Sanan Venkatesh ◽  
Rahat Hasan ◽  
Jake T Herb ◽  
Katia de Paiva Lopes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cell Types ◽  
Lumbar Spinal Cord ◽  
Gene Expression Response ◽  
Expression Response ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. We used 380 post-mortem tissue RNA-seq transcriptomes from 154 ALS cases and 49 control individuals from cervical, thoracic, and lumbar spinal cord segments to investigate the gene expression response to ALS. We observed an increase in microglia and astrocyte expression, accompanied by a decrease in oligodendrocytes. By creating a gene co-expression network in the ALS samples, we identify several activated microglia modules that negatively correlate with retrospective disease duration. We map molecular quantitative trait loci and find several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell-types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how repeat expansions that alter splicing of C9orf72 are tagged by common variants, and use this to suggest ATXN3 as a putative risk gene.

scholarly journals Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 21 (3) ◽  
pp. 1107 ◽  
Author(s):  
Elodie Martin ◽  
William Cazenave ◽  
Anne-Emilie Allain ◽  
Daniel Cattaert ◽  
Pascal Branchereau
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
High Performance ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Lumbar Spinal Cord ◽  
Spinal Motoneurons ◽  
Chloride Homeostasis ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of paramount importance to identify the primary defects that underlie this condition and to determine how these deficits lead to a cycle of deterioration. We recently demonstrated that prenatal E17.5 lumbar spinal motoneurons (MNs) from SOD1G93A mice exhibit a KCC2-related alteration in chloride homeostasis, i.e., the EGABAAR is more depolarized than in WT littermates. Here, using immunohistochemistry, we found that the SOD1G93A lumbar spinal cord is less enriched with 5-HT descending fibres than the WT lumbar spinal cord. High-performance liquid chromatography confirmed the lower level of the monoamine 5-HT in the SOD1G93A spinal cord compared to the WT spinal cord. Using ex vivo perforated patch-clamp recordings of lumbar MNs coupled with pharmacology, we demonstrated that 5-HT strongly hyperpolarizes the EGABAAR by interacting with KCC2. Therefore, the deregulation of the interplay between 5-HT and KCC2 may explain the alteration in chloride homeostasis detected in prenatal SOD1G93A MNs. In conclusion, 5-HT and KCC2 are two likely key factors in the presymptomatic phase of ALS, particular in familial ALS involving the SOD1G93A mutation.

scholarly journals Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hiroyasu Komiya ◽  
Hideyuki Takeuchi ◽  
Yuki Ogawa ◽  
Kosuke Suzuki ◽  
Akihiro Ogasawara ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Function ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Lumbar Spinal Cord ◽  
Primary Microglia ◽  
Tnf Α ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

AbstractNeuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1G93A Tg mice). We generated IL-19–deficient SOD1G93A Tg (IL-19−/−/SOD1G93A Tg) mice by crossing SOD1G93A Tg mice with IL-19−/− mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1G93A Tg mice and IL-19−/−/SOD1G93A Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1G93A Tg mice than in wild-type mice. Unexpectedly, IL-19−/−/SOD1G93A Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1G93A Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line–derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19−/−/SOD1G93A Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.

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