Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons

Gene Therapy ◽  
2021 ◽  
Author(s):  
Barış Genç ◽  
Javier H. Jara ◽  
Santana S. Sanchez ◽  
Amiko K. B. Lagrimas ◽  
Öge Gözütok ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Motor Neurons ◽  
Upper Motor Neurons ◽  
Cellular Integrity ◽  
Necessary And Sufficient

scholarly journals Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS

2021 ◽  
Vol 11 (5) ◽  
pp. 578
Author(s):  
Oge Gozutok ◽  
Benjamin Ryan Helmold ◽  
P. Hande Ozdinler
Keyword(s):  
Motor Neurons ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Cortical Neurons ◽  
Therapeutic Interventions ◽  
Functional Identification ◽  
Protein Protein Interaction ◽  
Cellular Events ◽  
Interaction Domains ◽  
Upper Motor Neurons

Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions.

scholarly journals Spinal BDNF-induced phrenic motor facilitation requires PKCθ activity

2017 ◽  
Vol 118 (5) ◽  
pp. 2755-2762 ◽  
Author(s):  
Ibis M. Agosto-Marlin ◽  
Gordon S. Mitchell
Keyword(s):  
Motor Neurons ◽  
Akt Signaling ◽  
Signaling Cascades ◽  
Receptor Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Inhibitory Peptide ◽  
Downstream Signaling ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Necessary And Sufficient

Spinal brain-derived neurotrophic factor (BDNF) is necessary and sufficient for certain forms of long-lasting phrenic motor facilitation (pMF). BDNF elicits pMF by binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), on phrenic motor neurons, potentially activating multiple downstream signaling cascades. Canonical BDNF/TrkB signaling includes the 1) Ras/RAF/MEK/ERK MAP kinase, 2) phosphatidylinositol 3‐kinase (PI3K)/Akt, and 3) PLCγ/PKC pathways. Here we demonstrate that spinal BDNF-induced pMF requires PLCγ/PKCθ in normal rats but not MEK/ERK or PI3K/Akt signaling. Cervical intrathecal injections of MEK/ERK (U0126) or PI3K/Akt (PI-828; 100 μM, 12 μl) inhibitor had no effect on BDNF-induced pMF (90 min after BDNF; U0126 + BDNF: 59 ± 14%, PI-828 + BDNF: 59 ± 8%, inhibitor vehicle + BDNF: 56 ± 7%; all P ≥ 0.05). In contrast, PKCθ inhibition with theta inhibitory peptide (TIP; 0.86 mM, 12 μl) prevented BDNF-induced pMF (90 min after BDNF; TIP + BDNF: −2 ± 2%; P ≤ 0.05 vs. other groups). Thus BDNF-induced pMF requires downstream PLCγ/PKCθ signaling, contrary to initial expectations. NEW AND NOTEWORTHY We demonstrate that BDNF-induced pMF requires downstream signaling via PKCθ but not MEK/ERK or PI3K/Akt signaling. These data are essential to understand the sequence of the cellular cascade leading to BDNF-dependent phrenic motor plasticity.

Motor neuron disease

2018 ◽  
Author(s):  
Martin R. Turner
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Corticospinal Tract ◽  
Muscular Atrophy ◽  
Muscle Denervation ◽  
Genetic Overlap ◽  
Upper Motor Neurons ◽  
Primary Lateral ◽  
Lateral Sclerosis

Motor neuron disease (MND) is characterized by progressive muscular weakness due to simultaneous degeneration of lower and upper motor neurons (L/UMNs). Involvement of LMNs, arising from the anterior horns of the spinal cord and brainstem, leads to secondary wasting as a result of muscle denervation. Involvement of the UMNs of the motor cortex and corticospinal tract results in spasticity. In ~85% of cases, there is clear clinical involvement of both, and the condition is termed ‘amyotrophic lateral sclerosis’ (ALS; a term often used synonymously with MND). In ~13% of cases, there may be only LMN signs apparent, in which case the condition is termed ‘progressive muscular atrophy’, although such cases have a natural history that is to largely identical to that of ALS. In a very small group of patients (~2%), there are only UMN signs for at least the first 4 years, in which case the condition is termed ‘primary lateral sclerosis’; such cases have a uniformly slower progression. There is clinical, neuropathological, and genetic overlap between MND and some forms of frontotemporal dementia.

scholarly journals MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Javier H. Jara ◽  
Mukesh Gautam ◽  
Nuran Kocak ◽  
Edward F. Xie ◽  
Qinwen Mao ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Cells ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Neuroinflammatory Response ◽  
Upper Motor Neurons ◽  
Als Patients ◽  
Betz Cells

Abstract Background The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies. Methods We investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43A315T-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest. Results We detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased. Conclusions There is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.

scholarly journals Non-viral gene therapy that targets motor neurons in vivo

2014 ◽  
Vol 7 ◽  
Author(s):  
Mary-Louise Rogers ◽  
Kevin S. Smith ◽  
Dusan Matusica ◽  
Matthew Fenech ◽  
Lee Hoffman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Motor Neurons ◽  
Viral Gene ◽  
Viral Gene Therapy

scholarly journals Acupuncture treatment for spasticity after brain injury

2021 ◽  
Vol 9 (1) ◽  
pp. 60-71
Author(s):  
Rong Xie ◽  
Yifei Wang ◽  
Jianghong He ◽  
Yi Yang
Keyword(s):  
Brain Injury ◽  
Motor Neurons ◽  
Acupuncture Treatment ◽  
Neurological Sequela ◽  
Positive Effects ◽  
Randomized Controlled ◽  
Involuntary Muscle ◽  
Nervous System Function ◽  
Upper Motor Neurons ◽  
Clinical Experiments

Spasticity after brain injury is a neurological sequela caused by damage to upper motor neurons. The primary symptoms are involuntary muscle activity, decreased muscle strength, and joint contracture. Acupuncture as a therapeutic method to regulate central nervous system function has been studied widely in recent years. Many clinical experiments have proved that acupuncture has positive effects on spasticity after brain injury. In this review, we discuss recent research of acupuncture treatment and the need for large randomized controlled trials.

scholarly journals A novel temporal identity window generates alternating cardinal motor neuron subtypes in a single progenitor lineage

2020 ◽  
Author(s):  
Austin Seroka ◽  
Rita M Yazejian ◽  
Sen-Lin Lai ◽  
Chris Q Doe
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Target Selection ◽  
Oblique Muscle ◽  
Spatial Patterning ◽  
Temporal Patterning ◽  
Neuron Morphology ◽  
Temporal Identity ◽  
Necessary And Sufficient

AbstractSpatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. These mechanisms generate cardinal classes of motor neurons (sharing a transcription factor identity and common muscle group targets). In Drosophila, two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal muscles and Nkx6+ motor neurons projecting to ventral muscles. The Drosophila neuroblast 7-1 (NB7-1) lineage generates distinct Eve+ motor neurons via the temporal transcription factor (TTF) cascade Hunchback (Hb)-Krüppel (Kr)-Pdm-Castor (Cas). Here we show that a newly discovered Kr/Pdm temporal identity window gives rise to an Nkx6+ Eve-motor neuron projecting to ventral oblique muscles, resulting in alternation of cardinal motor neuron subtypes from a single progenitor (Eve>Nkx6>Eve). We show that co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage and that Kr/Pdm act via Nkx6, which itself is necessary and sufficient for VO motor neuron identity. Lastly, Nkx6 is required for ventral oblique muscle targeting, thereby linking temporal patterning to motor neuron morphology and synaptic target selection. In conclusion, we show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm>Nkx6 pathway is necessary and sufficient to specify VO motor neuron identity and morphology.

scholarly journals Resurgent Na+ currents promote ultrafast spiking in projection neurons that drive fine motor control

2021 ◽  
Author(s):  
Benjamin M. Zemel ◽  
Alexander A. Nevue ◽  
Andre Dagostin ◽  
Peter V. Lovell ◽  
Claudio V. Mello ◽  
...  
Keyword(s):  
Motor Neurons ◽  
High Frequency ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Vocal Learning ◽  
Temporal Coding ◽  
Fine Motor ◽  
Inactivation Kinetics ◽  
Projection Neurons ◽  
Upper Motor Neurons

AbstractThe underlying mechanisms that promote precise spiking in upper motor neurons controlling fine motor skills are not well understood. Here we report that projection neurons in the adult zebra finch song nucleus RA display: 1) robust high-frequency firing, 2) ultra-short half-width spike waveforms, 3) superfast Na+ current inactivation kinetics and 4) large resurgent Na+ currents (INaR). These spiking properties closely resemble those of specialized pyramidal neurons in mammalian motor cortex and are well suited for precise temporal coding. They emerge during the critical period for vocal learning in males but not females, coinciding with a complete switch of modulatory Na+ channel subunit expression from Navβ3 to Navβ4. Dynamic clamping and dialysis of Navβ4’s C-terminal peptide into juvenile RA neurons provide evidence that this subunit, and its associated INaR, promote neuronal excitability. We propose that Navβ4 underpins INaR that facilitates precise, prolonged, and reliable high-frequency firing in upper motor neurons.

scholarly journals Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons

2019 ◽  
Vol 20 (16) ◽  
pp. 3848 ◽  
Author(s):  
Baris Genc ◽  
Oge Gozutok ◽  
P. Hande Ozdinler
Keyword(s):  
Motor Neuron ◽  
Mouse Models ◽  
Motor Neurons ◽  
Cell Biology ◽  
Neuronal Degeneration ◽  
Cellular Level ◽  
Model Systems ◽  
Special Importance ◽  
Upper Motor Neurons ◽  
Lateral Sclerosis

Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in which initiation and modulation of voluntary movement is affected. Amyotrophic lateral sclerosis (ALS) is defined by the progressive degeneration of both the upper and lower motor neurons, whereas hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are characterized mainly by the loss of upper motor neurons. In an effort to reveal the cellular and molecular basis of neuronal degeneration, numerous model systems are generated, and mouse models are no exception. However, there are many different levels of complexities that need to be considered when developing mouse models. Here, we focus our attention to the upper motor neurons, which are one of the most challenging neuron populations to study. Since mice and human differ greatly at a species level, but the cells/neurons in mice and human share many common aspects of cell biology, we offer a solution by focusing our attention to the affected neurons to reveal the complexities of diseases at a cellular level and to improve translational efforts.

Neurobiology of Sensory Motor Systems and Internal Environment

2020 ◽  
pp. 60-79
Author(s):  
Pradeep Kallollimath
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Sensory Nerve ◽  
Muscle Fibres ◽  
Internal Environment ◽  
Motor Systems ◽  
Spinal Cord Segment ◽  
Sensory Motor ◽  
Dorsal Columns ◽  
Upper Motor Neurons

Control of motor function—our activities like walking, lifting an object, writing, etc.—is accomplished through integrated and coordinated action of motor neurons. Motor neurons can be classified into two broad categories: upper motor neurons and lower motor neurons. Upper motor neurons have cell bodies in the motor cortex of brain and carry the impulses from cortex to spinal cord segment. Cell bodies of lower motor neurons are located in the anterior horn of spinal cord. Axons of lower motor neuron end in neuromuscular junction, and excitation of muscle fibres leads contraction of muscle. Different types of receptors carry different sensations like touch, pain, position, and vibration through sensory nerve fibres. Fibers mediating fine touch and proprioception ascend in the dorsal columns to the medulla, where they synapse in the gracile and cuneate nuclei. This chapter explores the neurobiology of sensory motor systems and the internal environment.

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