scholarly journals Illuminating ALS Motor Neurons With Optogenetics in Zebrafish

2021 ◽  
Vol 9 ◽  
Author(s):  
Kazuhide Asakawa ◽  
Hiroshi Handa ◽  
Koichi Kawakami
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Rna Binding ◽  
The Body ◽  
Optical Methods ◽  
Light Illumination ◽  
Whole Cells ◽  
Spinal Motor Neurons ◽  
Spinal Motor

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Spinal motor neurons align along the spinal cord length within the vertebral column, and extend long axons to connect with skeletal muscles covering the body surface. Due to this anatomy, spinal motor neurons are among the most difficult cells to observe in vivo. Larval zebrafish have transparent bodies that allow non-invasive visualization of whole cells of single spinal motor neurons, from somas to the neuromuscular synapses. This unique feature, combined with its amenability to genome editing, pharmacology, and optogenetics, enables functional analyses of ALS-associated proteins in the spinal motor neurons in vivo with subcellular resolution. Here, we review the zebrafish skeletal neuromuscular system and the optical methods used to study it. We then introduce a recently developed optogenetic zebrafish ALS model that uses light illumination to control oligomerization, phase transition and aggregation of the ALS-associated DNA/RNA-binding protein called TDP-43. Finally, we will discuss how this disease-in-a-fish ALS model can help solve key questions about ALS pathogenesis and lead to new ALS therapeutics.

scholarly journals The manipulation of spinal motor neuron axonal growth promotes spinal cord repair

2021 ◽  
Author(s):  
Feng Wang ◽  
Xinya Fu ◽  
Meiemei Li ◽  
Xingran Wang ◽  
Jile Xie ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Axonal Regeneration ◽  
Axonal Growth ◽  
Treatment Method ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Cord Injury ◽  
Spinal Cord Repair

The loss of motor function in patients with spinal cord injury (SCI) is primarily due to the severing of the corticospinal tract (CST). Spinal motor neurons are located in the anterior horn of the spinal cord, and as the lower neurons of the CST, they control voluntary movement. Furthermore, its intrinsic axonal growth ability is significantly stronger than that of cerebral cortex pyramid neurons, which are the upper CST neurons. Therefore, we established an axonal regeneration model of spinal motor neurons to investigate the feasibility of repairing SCI by promoting axonal regeneration of spinal motor neurons. We demonstrated that conditionally knocking out pten in mature spinal motor neurons drastically enhanced axonal regeneration in vivo, and the regenerating axons of the spinal motor neurons re-established synapses with other cells in the damaged spinal cord. Thus, this strategy may serve as a novel and effective treatment method for SCI.

scholarly journals Optogenetic modulation of TDP-43 oligomerization fast-forwards ALS-related pathologies in the spinal motor neurons

2019 ◽  
Author(s):  
Kazuhide Asakawa ◽  
Hiroshi Handa ◽  
Koichi Kawakami
Keyword(s):  
Motor Neurons ◽  
Light Illumination ◽  
Short Term ◽  
Spinal Motor Neuron ◽  
Spinal Motor Neurons ◽  
Intrinsically Disordered ◽  
Spinal Motor ◽  
Lateral Sclerosis

AbstractCytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS), yet the mechanisms and cellular outcomes of TDP-43 pathology remain largely elusive. Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defect associated with myofiber denervation. In contrast, opTDP-43 forms pathological aggregates in the cytoplasm after longer-term illumination and seeds non-optogenetic TDP-43 aggregation. Furthermore, we find that an ALS-linked mutation in the intrinsically disordered region (IDR) exacerbates the light-dependent opTDP-43 toxicity on locomotor behavior. Together, our results propose that IDR-mediated TDP-43 oligomerization triggers both acute and long-term pathologies of motor neurons, which may be relevant to the pathogenesis and progression of ALS.

DL -Homocysteic acid application disrupts calcium homeostasis and induces degeneration of spinal motor neurons in vivo

2002 ◽  
Vol 103 (5) ◽  
pp. 428-436 ◽  
Author(s):  
Róbert Adalbert ◽  
József Engelhardt ◽  
László Siklós
Keyword(s):  
Motor Neurons ◽  
Calcium Homeostasis ◽  
Homocysteic Acid ◽  
Spinal Motor Neurons ◽  
Spinal Motor

scholarly journals Glycine-specific synapses in rat spinal cord. Identification by electron microscope autoradiography.

1976 ◽  
Vol 68 (2) ◽  
pp. 389-395 ◽  
Author(s):  
D L Price ◽  
A Stocks ◽  
J W Griffin ◽  
A Young ◽  
K Peck
Keyword(s):  
Spinal Cord ◽  
Electron Microscope ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Uptake System ◽  
Electron Microscope Autoradiography ◽  
Spinal Motor Neurons ◽  
Microscope Autoradiography ◽  
Axodendritic Synapses

Glycine, an inhibitory transmitter in spinal cord, is taken up into specific nerve terminals by means of a unique high-affinity uptake system. In this study, [3H]glycine was directly microinjected into rat ventral horn in vivo and electron microscope autoradiography used to localize the label in various anatomic compartments. Quantiative analysis showed that [3H]glycine labeled a high proportion of axosomatic and axodendritic synapses which presumably act to inhibit spinal motor neurons.

scholarly journals Single-cell transcriptomic analysis of the adult mouse spinal cord

2020 ◽  
Author(s):  
Jacob A. Blum ◽  
Sandy Klemm ◽  
Lisa Nakayama ◽  
Arwa Kathiria ◽  
Kevin A. Guttenplan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Single Cell ◽  
Motor Neurons ◽  
The Body ◽  
Molecular Heterogeneity ◽  
Spinal Motor Neuron ◽  
Spinal Motor ◽  
Full Complement ◽  
Adult Spinal Cord

AbstractThe spinal cord is a fascinating structure responsible for coordinating all movement in vertebrates. Spinal motor neurons control the activity of virtually every organ and muscle throughout the body by transmitting signals that originate in the spinal cord. These neurons are remarkably heterogeneous in their activity and innervation targets. However, because motor neurons represent only a small fraction of cells within the spinal cord and are difficult to isolate, the full complement of motor neuron subtypes remains unknown. Here we comprehensively describe the molecular heterogeneity of motor neurons within the adult spinal cord. We profiled 43,890 single-nucleus transcriptomes using fluorescence-activated nuclei sorting to enrich for spinal motor neuron nuclei. These data reveal a transcriptional map of the adult mammalian spinal cord and the first unbiased characterization of all transcriptionally distinct autonomic and somatic spinal motor neuron subpopulations. We identify 16 sympathetic motor neuron subtypes that segregate spatially along the spinal cord. Many of these subtypes selectively express specific hormones and receptors, suggesting neuromodulatory signaling within the autonomic nervous system. We describe skeletal motor neuron heterogeneity in the adult spinal cord, revealing numerous novel markers that distinguish alpha and gamma motor neurons—cell populations that are specifically affected in neurodegenerative disease. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neurons. Collectively, these data provide a single-cell transcriptional atlas for investigating motor neuron diversity as well as the cellular and molecular basis of motor neuron function in health and disease.

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