[Biochemistry of motor neurons--in relation to motor neuron diseases].
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4-Hydroxyaminoquinoline-1-oxide↗
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Results for “Motor Neurons”
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Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.
Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.
Humans↗
Changes in motor unit populations in motor neurone disease.
In motor neurone disease changes in the functional properties of motor units, including the surface voltage, latency, conduction velocity, and response to repetitive stimulation, were investigated. Progression was marked by motor unit loss, increase in the proportion of larger motor unit potentials, and inclusion of motor unit potentials larger than normal in the remaining motor unit population. Even late in the disease, motor unit potentials with a low surface voltage persisted. The relationship between motor unit potentials, surface voltage, and latency, present in control subjects, broke down in motor neurone disease, large motor unit potentials having abnormally long latencies and small motor unit potentials unexpectedly short latencies. Amplitude decrements were more frequent and severe in motor unit potentials at later stages in the disease, particularly in those units with lower surface voltages. In one surviving motor unit potential there was evidence suggestive of functional recovery. The observations point to complex changes in the functional properties of motor units in motor neurone disease.
Cell Count↗
Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system.
Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in RET account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound RET enhancer (MCS+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigated the role of this enhancer by generating mice carrying a deletion of the orthologous Ret mcs+9.7 enhancer (Δmcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrated that enhancer deletion reduced Ret expression by 8% without altering ENS cell composition. However, reduced Ret expression was restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type-specific enhancer activity. To determine the functional consequences of further reducing Ret dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a Ret coding null allele (+/Δmcs+9.7;+/CFP). These mice exhibited additive reductions in Ret expression, altered Sox10 expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type-specific role for the mcs+9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by >50% loss of Ret function.
Journal Article↗
The structure and function of serially homologous leg motor neurons in the locust. I. Anatomy.
Twenty-one prothoracic and 17 mesothoracic motor neurons innervating leg muscles have been identified physiologically and subsequently injected with dye from a microelectrode. A tract containing the primary neurites of motor neurons innervating the retractor unquis, levator and depressor tarsus, flexor tibiae, and reductor femora is described. All motor neurons studied have regions in which their dendritic branches overlap with those of other leg motor neurons. Identified, serially homologous motor neurons in the three thoracic ganglia were found to have: (1) cell bodies at similar locations and morphologically similar primary neurites (e.g., flexor tibiae motor neurons), (2) cell bodies at different locations in each ganglion and morphologically different primary neurites in each ganglion (e.g., fast retractor unguis motor neurons), or (3) cell bodies at similar locations and morphologically similar primary neurites but with a functional switch in one ganglion relative to the function of the neurons in the other two ganglia. As an example of the latter, the morphology of the metathoracic slow extensor tibiae (SETi) motor neurons was similar to that of pro- and mesothoracic fast extensor tibiae (FETi) motor neurons. Similarly the metathoracic FETi bears a striking resemblance to the pro- and the mesothoracic SETi. It is proposed that in the metathoracic ganglion the two extensor tibiae motor neurons have switched functions while retaining similar morphologies relative to the structure and function of their pro- and mesothoracic serial homologues.
Animals↗
Cholinergic motor neurones in the stomatogastric system of the lobster.
1. A study of the neurotransmitters used by each of the eleven types of excitatory motor neurones (identified according to the muscle innervated) of the lobster stomatogastric ganglion was undertaken. 2. The dorsal dilator muscle is innervated by the two motor neurones designated 'PD'. Bath and iontophoretic applications of acetylcholine (ACh) produce contractures and depolarizations respectively in the dorsal dilator muscle. 3. Pharmacological experiments support the cholinergic nature of the excitatory junctional potentials (e.j.p.s) recorded in the dorsal dilator muscle when the PD motor nerve is stimulated. 4. The apparent reversal potentials for the e.j.p.s and the iontophoretic ACh response in the dorsal dilator muscle are the same. 5. On the basis of choline acetyltransferase assays on identified stomatogastric ganglion motor neurone somata and tension measurements on the muscles innervated by each type of stomatogastric ganglion motor neurone, a transmitter candidate was established for each type of motor neurone. Motor neurones named VD, LPG, GM, MG, LG, and DG are putatively cholinergic. L-Glutamate is a transmitter candidate for the motor neurones called LP, PY, IC, and AM. 6. Potential correlations between the distribution of putatively cholinergic and glutaminergic motor neurones and the electrical coupling among the stomatogastric ganglion motor neurones are discussed.
Acetylcholine↗
Histochemical and morphologic changes in skeletal muscle following cervical cord injury: a study of upper and lower motor neuron lesions.
The effects of upper and lower motor neuron lesions on human skeletal muscles and muscle spindles were studied using histochemical and morphometric techniques. In the lower motor neuron lesions, the muscle fibers showed group atrophy, fiber type grouping and target fibers. The muscle spindle demonstrated thickening of the capsule, degeneration of the nuclear chain fibers, targeting and splitting of the bag fibers. In the upper motor neuron lesion, the muscles showed group atrophy with histochemical evidence of preferential type II fiber involvement. Histometrics, however, failed to demonstrate type II fiber atrophy but showed hypertrophy of type I fibers. The muscle spindles only showed increased number of intrafusal fibers.
Adenosine Triphosphatases↗
The specificity of innervation of regenerating motor neurons in the cockroach.
The pattern of neuromuscular connections of cockroach motor neurons regenerating to an intact mesothoracic leg after crushing nerve 5 has been investigated. While a number of anatomically identified motor neurons reestablished functional connections with their correct target muscles, some of the same and other motor neurons were found to functionally innervate inappropriate muscles. Muscles, and in some cases individual fibres, were often simultaneously innervated by both correct and foreign motor neurons. The frequency of innervation errors decreased with increasing post-operative times, although some errors persisted to the latest stages examined (227 days).
Animals↗
The structure and function of serially homologous leg motor neurons in the locust. II. Physiology.
Simultaneous intracellular recordings were made from pairs of motor neurons in the pro- or mesothoracic ganglion of the locust. Though central connections were sought between pairs of motor neurons, none were found. This is in sharp contrast to the findings that flexor and extensor tibiae neurons in the metathoracic ganglion make certain connections between themselves (Hoyle and Burrows, 1973; Heitler and Burrows, 1977a). As the previously mentioned authors believed that the metathoracic flexor-extensor connections were used as part of the motor program for jumping and kicking, the present results strongly support their hypothesis. Common PSPs have been found in a variety of pairs of motor neurons. Of note are common PSPs of the same sign to antagonists. Different innervation patterns have been found for the flexor and extensor muscles. It is proposed that serially homologous motor neurons serving similar functions are, to a first approximation, similar in the locust. Serially homologous motor neurons serving different functions will, in most cases, have altered structures and/or functions.
Animals↗
Graded synaptic transmission between local interneurones and motor neurones in the metathoracic ganglion of the locust.
1. In the metathoracic ganglion of the locust some neurones can effect changes in the membrane potential of identified post-synaptic motor neurones without themselves spiking. 2. These 'non-spiking' neurones have processes only within the metathoracic ganglion, and therefore are local intraganglionic interneurones. 3. The absence of spikes in the interneurones reflects their normal physiological state and is not due to the experimental conditions. 4. When the interneurones are depolarized by the injection of current pulses lasting several hundred milliseconds, post-synaptic motor neurones are either depolarized, or hyperpolarized, for the duration of the pulse. 5. The magnitude of the change in post-synaptic voltage is graded according to the amount of presynaptic current. 6. A number of physiological tests indicate that the graded effects upon motor neurones are mediated by chemical synaptic transmission. For example, an evoked hyperpolarization of a motor neurone can be reversed in polarity by simultaneously hyperpolarizing the motor neurone with injected current. 7. At their resting potential some interneurones tonically release sufficient transmitter to have a measurable post-synaptic effect. The injection of depolarizing and hyperpolarizing currents into these interneurones effects opposite changes in post-synaptic potential. 8. Other interneurones must be depolarized from resting potential before a post-synaptic effect is observed, and hyperpolarizing currents have no post-synaptic effect. In these interneurones it is estimated that a depolarization of only 2 mV is sufficient to effect the release of transmitter. 9. The membrane potentials of non-spiking interneurones can fluctuate by as much as 15 mV during active movements of the hind legs and individual p.s.p.s as large as 5 mV can be recorded. Therefore, summed p.s.p.s or even single ones are expected to be the electrophysiological signals effecting transmitter release from these interneurones.
Action Potentials↗
Identification of respiratory motor neurons in the carp and determination of their firing characteristics and interconnections.
Motor neurons of the respiratory muscles of the carp, located in the medulla oblongata, are identified with a signal averaging technique. Analysis of the firing characteristics of these neurons provides data on their activity patterns under different circumstances. The results show that, on the one hand, the number of spikes a motor neuron fires per respiratory cycle depends on the respiratory intensity, and can even be as low as one action potential per respiration. On the other hand, with constant respiratory intensity, the activity of individual motor neurons can stop and be resumed again in periods of several minutes. During mechanical loading of respiration, action potential synchronization between specific respiratory muscles takes place. Possible neuronal circuits causing this synchronization, which is thought to increase the coordination of the muscular effort, are discussed.
Animals↗
Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.
We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.
Journal Article↗
Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.
Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.
Humans↗
A motor neuron involved in two centrally generated motor patterns by means of two different spike initiating sites.
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Action Potentials↗
Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.
OBJECTIVE: To systematically investigate Somatosensory Evoked Potential (SEP) abnormalities in a large cohort of patients with Motor Neuron Disease (MND), and to explore their relationship with Motor Evoked Potentials (MEPs) and clinical phenotypes. METHODS: We retrospectively analyzed 267 patients with confirmed MND who underwent standardized SEPs and transcranial magnetic stimulation. Patients were divided into pure/predominant Upper Motor Neuron (UMN) and pure/predominant Lower Motor Neuron/Amyotrophic Lateral Sclerosis (LMN/ALS) groups. SEP abnormalities were assessed using internal normative data, including prolonged latencies, reduced amplitudes, and increased N20-P25 amplitudes. MEPs were classified semi-quantitatively as normal or abnormal by independent raters. RESULTS: At least one SEP abnormality was detected in 75 % of patients, with no significant differences between the UMN and LMN/ALS groups. Increased N20-P25 amplitudes were observed in both phenotypes, suggesting widespread sensory cortical hyperexcitability across the MND spectrum. In contrast, abnormal MEPs were significantly more frequent in UMN patients (p < 0.001). No significant association was found between SEP abnormalities and MEP findings. Upper- and lower-limb SEP latencies were strongly correlated (all p < 0.001), whereas increased SEP amplitudes did not correlate with latency abnormalities. CONCLUSIONS: SEP abnormalities are highly prevalent in MND and appear largely independent from corticospinal dysfunction. Increased SEP amplitudes likely reflect primary cortical sensory hyperexcitability rather than impaired sensory conduction. SIGNIFICANCE: These findings support the concept of MND as a multisystem network disorder that involves sensory cortical circuits and highlight the role of SEPs in the diagnostic workup.
Humans↗
Interactions among an ensemble of chordotonal organ receptors and motor neurons of the crayfish claw.
1. Action potentials of crayfish propodite-dactyl (PD) chordotonal organ receptors and two claw motor neurons, the opener inhibitor (OI) and slow closer excitor CE) were simultaneously monitored during imposed step and ramp movements of the dactyl or while the dactyl was held at various positions. 2. The activities of the cells during imposed displacements were analyzed using peristimulus time histograms and response and contour planes. The proprioceptive fields (PFs) of individual receptors resemble components of the more complex motor neuron PFs. Some receptors are briefly active after each successive opening step, while others do not respond to steps near the closed position but respond as the joint angle increases, becoming active when the claw is held open. Another type of receptor responds to closing movements. 3. Interactions among the various types of receptors and the two motor neurons were detected and analyzed by various statistical methods and intracellular recording techniques. The results indicate that receptors activated during opening movements and when the dactyl is held at open positions excite OI and CE via divergent functional connections. The efficacies of the connections made by a receptor may differ. Receptors activated by closing movements produce hyperpolarizing synaptic potentials in both efferents, possible directly or via interneurons. 4. It is concluded that several types of chordotonal organ receptors form an ensemble of parallel input channels, which modulates the activities of OI and CE and contributes to the generation of the spatial-temporal nonuniformities of their proprioceptive reflex responses.
Animals↗
Macroglobulinemia Waldenström and motor neuron syndrome.
One patient suffering from macroglobulinemia Waldenström developed a neurological disease which may be a previously unrecognized paramalignant phenomenon in this disorder. The clinical symptoms and signs indicate a motor neuron syndrome and autopsy revealed degeneration of ventral and lateral funicles in the spinal cord, loss of ventral motor neurons, degeneration of ventral nerve roots and muscular atrophy. The rather low incidence of macroglobulinemia and motor neuron disease suggest some causal relationship rather than a sporadic occurrence of two disorders in the same patient.
Aged↗
Proprioceptive fields of crayfish claw motor neurons.
1. Action potentials of crayfish claw motor neurons were recorded during both imposed constant-velocity displacements and imposed alternating sequences of opening and closing step movements of the dactyl. 2. Peristimulus time (PST) histograms show that the firing probabilities of two neurons, the opener inhibitor (OI) and the slow closer excitor (CE) consistently increased during opening ramp movements and declined during closing ramp movements. Hyperpolarizing synaptic potentials were observed in both cells during closing movements. 3. The proprioceptive field organizations of OI and CE were analyzed with response planes and contour planes. Each PST histogram in a plane displays the firing probability of the neuron as a function of time following step displacements at a given position. A relatively uniform early primary response followed each successive opening step. The probability of occurrence of later activity, when present, usually became more pronounced as the joint angle increased. Often both cells were silent during closing steps; when the cells were active, their firing probabilities were highest at the more open joint angles. 4. When both OI and CE were active, their spike trains were usually temporally correlated. 5. The other claw efferents did not respond to imposed movements in a consistent manner. When CE was active it was most likely to respond to closing movements near the closed position. 6. It is concluded that OI and CE are strongly and similarly influenced by proprioceptive reflexes. The responses of the two cells to imposed dactyl movements change as a function of joint angle, time after movement, and direction of movement.
Animals↗