scholarly journals Activity-Driven Synaptic and Axonal Degeneration in Canine Motor Neuron Disease

2004 ◽  
Vol 92 (2) ◽  
pp. 1175-1181 ◽  
Author(s):  
Dario I. Carrasco ◽  
Mark M. Rich ◽  
Qingbo Wang ◽  
Timothy C. Cope ◽  
Martin J. Pinter
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Motor Axon ◽  
Medial Gastrocnemius ◽  
Neuron Activity ◽  
Functional Changes ◽  
Unit Function

The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.

scholarly journals Reduced Endplate Currents Underlie Motor Unit Dysfunction in Canine Motor Neuron Disease

2002 ◽  
Vol 88 (6) ◽  
pp. 3293-3304 ◽  
Author(s):  
Mark M. Rich ◽  
Robert. F. Waldeck ◽  
Linda C. Cork ◽  
Rita J. Balice-Gordon ◽  
Robert E. W. Fyffe ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit ◽  
Conduction Velocity ◽  
Motor Neurons ◽  
Muscle Fiber ◽  
Muscular Atrophy ◽  
Motor Units ◽  
Postnatal Maturation ◽  
Axonal Conduction

Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant degenerative disorder of motor neurons. In homozygous animals, motor units produce decreased force output and fail during repetitive activity. Previous studies suggest that decreased efficacy of neuromuscular transmission underlies these abnormalities. To examine this, we recorded muscle fiber endplate currents (EPCs) and found reduced amplitudes and increased failures during nerve stimulation in homozygotes compared with wild-type controls. Comparison of EPC amplitudes with muscle fiber current thresholds indicate that many EPCs from homozygotes fall below threshold for activating muscle fibers but can be raised above threshold following potentiation. To determine whether axonal abnormalities might play a role in causing motor unit dysfunction, we examined the postnatal maturation of axonal conduction velocity in relation to the appearance of tetanic failure. We also examined intracellularly labeled motor neurons for evidence of axonal neurofilament accumulations, which are found in many instances of motor neuron disease including HCSMA. Despite the appearance of tetanic failure between 90 and 120 days, average motor axon conduction velocity increased with age in homozygotes and achieved adult levels. Normal correlations between motor neuron properties (including conduction velocity) and motor unit properties were also observed. Labeled proximal motor axons of several motor neurons that supplied failing motor units exhibited little or no evidence of axonal swellings. We conclude that decreased release of transmitter from motor terminals underlies motor unit dysfunction in HCSMA and that the mechanisms determining the maturation of axonal conduction velocity and the pattern of correlation between motor neuron and motor unit properties do not contribute to the appearance or evolution of motor unit dysfunction.

scholarly journals Muscle Expression of Mutant Androgen Receptor Accounts for Systemic and Motor Neuron Disease Phenotypes in Spinal and Bulbar Muscular Atrophy

Neuron ◽  
2014 ◽  
Vol 82 (2) ◽  
pp. 295-307 ◽  
Author(s):  
Constanza J. Cortes ◽  
Shuo-Chien Ling ◽  
Ling T. Guo ◽  
Gene Hung ◽  
Taiji Tsunemi ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Muscular Atrophy ◽  
Disease Phenotypes

scholarly journals Motor neuron disease presenting with fetal akinesia

2018 ◽  
Vol 45 (S1) ◽  
pp. S4-S4
Author(s):  
P. Shannon ◽  
D. Chitayat ◽  
K. Chong ◽  
C. Dunham ◽  
C. Fallet-Bianco
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Globus Pallidus ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neuronal Loss ◽  
Ischemic Injury ◽  
Neuroaxonal Dystrophy ◽  
Lysosomal Storage ◽  
Whole Exome

By contrast to infantile spinal muscular atrophy, which usually links to deletions in the SMN genes, fetal onset motor neuron disease is poorly reported. We collected a series of twelve cases of fetal arthrogryposis (16-31 weeks gestational age) with fetal motor neuron disease and excluded infectious diseases, lysosomal storage disease and neuroaxonal dystrophy. Of these twelve, 3 were thought to be ischemic in nature with microvascular alterations and systemic or central nervous system ischemic injury. The remaining 9 all displayed marked reduction in anterior horn motor neurons. Of these 9, four demonstrated mineralised neurons, four demonstrated either neuronal loss or cavitation in the globus pallidus, and in two, degenerating neurons were detectable in the brainstem or globus pallidus. Specific sequencing of SMN1 was performed in 6 of 9 and was reported as normal. Whole exome sequencing was performed in 4 without definitive diagnosis. We conclude that fetal motor neuron disease can be distinguished from ischemic injury, is morphologically heterogeneous, may affect the globus pallidus and is rarely linked to SMN1 mutations.

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 Traumatic Brain Injury Results in Cellular, Structural and Functional Changes Resembling Motor Neuron Disease

2016 ◽  
Author(s):  
David K. Wright ◽  
Shijie Liu ◽  
Chris van der Poel ◽  
Stuart J. McDonald ◽  
Rhys D. Brady ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Functional Changes

scholarly journals Inherited Motor Neuron Disease in Domestic Cats: A Model of Spinal Muscular Atrophy

2005 ◽  
Vol 57 (3) ◽  
pp. 324-330 ◽  
Author(s):  
Qianchuan He ◽  
Charles Lowrie ◽  
G Diane Shelton ◽  
Rudy J Castellani ◽  
Marilyn Menotti-Raymond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Muscular Atrophy ◽  
Domestic Cats

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

2000 ◽  
Vol 47 (5) ◽  
pp. 596-605 ◽  
Author(s):  
Rita J. Balice-Gordon ◽  
Daniel B. J. Smith ◽  
Joshua Goldman ◽  
Linda C. Cork ◽  
Anne Shirley ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit

scholarly journals Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

2021 ◽  
Vol 13 (578) ◽  
pp. eabb6871
Author(s):  
Lingling Kong ◽  
David O. Valdivia ◽  
Christian M. Simon ◽  
Cera W. Hassinan ◽  
Nicolas Delestrée ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Radial Growth ◽  
Muscular Atrophy ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Motor Axon ◽  
Myelinated Axons ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Axon Development

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

Motor Neuron Disease (DRAFT)

2018 ◽  
Author(s):  
Tamara Kaplan ◽  
Tracey Milligan
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Muscular Atrophy ◽  
Lower Motor Neuron ◽  
Lateral Sclerosis

The video in this chapter explores motor neuron disease, including amytrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). It discusses the signs of upper motor neuron (UMN) and lower motor neuron (LMN) pathology, as well as Kennedy disease.

scholarly journals Motor unit behavior in canine motor neuron disease

1995 ◽  
Vol 15 (5) ◽  
pp. 3447-3457 ◽  
Author(s):  
MJ Pinter ◽  
RF Waldeck ◽  
N Wallace ◽  
LC Cork
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit
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