Ultrastructure of spinal anterior horn cells in human Niemann-Pick type C (NPC) patient and mouse model of NPC with retroposon insertion in NPC1 genes.

Niemann-Pick disease type C (NPC) is a neurovisceral lipid-storage disease. Although NPC patients show lipid storage in anterior horn cells of the spinal cord, little information is available regarding the electron microscopic analyses of the morphologies of intra-endosomal lipid like-materials in the anterior horn cells of NPC patients. In this study, we elucidated the intra-endosomal ultrastructures in spinal anterior horn cells in an NPC patient, as well as in mutant BALB/c NPC1-/- mice with a retroposon insertion in the NPC1 gene. These morphologies were classified into four types: vesicle, multiple concentric sphere (MCS), membrane, and rose flower. The percentages of the composition in the NPC patient and NPC1-/- mice were: vesicle (55.5% and 14.9%), MCS (15.7% and 3.4%), membrane (23.6% and 57.1%), and rose flower (5.2% and 24.6%), respectively. Formation of the intra-endosomal structures could proceed as follows: (i) a vesicle or MCS buds off the endosome into the lumen; (ii) when a vesicle breaks down, a membrane is formed; and (iii) after an MCS breaks down, a rose flower structure is formed. Our new finding in this study is that ultrastructural morphology is the same between the NPC patient and NPC1-/- mice, although there are differences in the composition.

Colocalization of Bunina bodies and TDP-43 inclusions in a case of sporadic amyotrophic lateral sclerosis with Lewy body-like hyaline inclusions.

Sporadic amyotrophic lateral sclerosis (sALS) is characterized pathologically by loss of upper and lower motor neurons with occurrence of transactivation response DNA-binding protein 43 kDa (TDP-43)-immunoreactive skein-like and round hyaline inclusions. Lewy body-like hyaline inclusions (LBHIs) are also found in a small proportion of sALS cases as well as in individuals with familial ALS with mutations in the Cu/Zu superoxide dismutase (SOD1) gene. LBHIs in sALS are immunopositive for TDP-43, but not for SOD1. The occurrence of Bunina bodies (BBs) is another key pathological feature of sALS. BBs are immunonegative for TDP-43 but immunopositive for cystatin C, transferrin, peripherin and sortilin-related receptor CNS expressed 2 (SorCS2). Despite differences between BBs and TDP-43 inclusions in terms of protein constituents and ultrastructure, the two inclusions are known to be linked. We recently encountered a case of sALS of 10 months duration in which many round hyaline inclusions, LBHIs and BBs were found in the anterior horn cells of the spinal cord. Our immunohistochemical and ultrastructural examinations revealed the presence of BBs within the skein-like and round hyaline inclusions, and in the LBHIs. Colocalization of BB-related proteins (cystatin C, transferrin and SorCS2) and TDP-43 was also confirmed in the halo of LBHIs as well as in the marginal portion of the skein-like and round hyaline inclusions. These findings suggest that there is some relationship between BBs and TDP-43-immunoreactive inclusions in terms of their formation processes.

Atypical lower motor neuron disease with enlargement of Nissl substance: Report of an autopsy case.

The patient was an 81-year-old woman diagnosed with atypical motor neuron disease who died after a long clinical course (7.5 years without mechanical assistance of ventilation) characterized by lower motor neuron signs and symptoms. Upper motor neuron signs and cognitive impairment were not apparent. Autopsy demonstrated severe neuronal loss in the anterior horn of the spinal cord, and some of the remaining neurons showed enlargement of Nissl substance and apparent thickening of the nuclear envelopes. No Bunina bodies, skein-like inclusions, or structures immunoreactive for phosphorylated transactivation response DNA-binding protein 43 were found. Immunoreactivity for superoxide dismutase-1 was focally seen in the enlarged Nissl substance. Ultrastructural examination demonstrated an increase of rough-surfaced endoplasmic reticulum (rough ER) and free ribosomes, disaggregation of polyribosomes, and dispersion of free ribosomes. Cisterns of rough ER were slightly dilated, and some of them were closely attached to the nuclear envelopes. Enlargement of Nissl substance may be related to "ER stress", and the abnormal findings of rough ER and free ribosomes may represent a degenerative process. However, another possibility, that they represent a compensatory hyperplastic change, cannot be excluded. The close attachment of cisterns of rough ER to the nuclear envelopes may be a mechanism to support or compensate for the abnormally-fragile nuclear envelopes.
.

Triggering of Autophagy by Baicalein in Response to Apoptosis after Spinal Cord Injury: Possible Involvement of the PI3K Activation.

High level apoptosis induced by spinal cord injury (SCI) evokes serious damage because of the loss and dysfunction of motor neurons. Our previous studies showed that inhibition of autophagy evokes the activation of apoptosis. Interestingly, Baicalein, a medicine with anti-apoptosis activity that is derived from the roots of herb Scutellaria baicalensis, largely induces autophagy by activating phosphatidylinositol 3-kinase (PI3K). In this study, we investigated the effects of intraperitoneal injection of Baicalein on autophagy and apoptosis in SCI mice and evaluated the relationship between autophagy and apoptosis. We demonstrated that Baicalein promoted the functional recovery of motor neurons at 7 d after SCI. In addition, Baicalein enhanced neuronal autophagy and the autophagy-related factor PI3K, while inhibiting the p62 protein. Baicalein treatment decreased neuronal apoptosis at 7 d after SCI. Moreover, when inhibiting autophagy, apoptosis was upgraded by Baicalein treatment after injury. Thus, Baicalein attenuated SCI by inducing autophagy to reduce apoptosis in neurons potentially via activating PI3K.

Unique nuclear vacuoles in the motor neurons of conditional ADAR2-knockout mice.

A reduction in adenosine deaminase acting on RNA 2 (ADAR2) activity causes the death of spinal motor neurons specifically via the GluA2 Q/R site-RNA editing failure in sporadic amyotrophic lateral sclerosis (ALS). We studied, over time, the spinal cords of ADAR2-knockout mice, which are the mechanistic model mice for sporadic ALS, using homozygous ADAR2(flox/flox)/VAChT-Cre.Fast (AR2), homozygous ADAR2(flox/flox)/VAChT-Cre.Slow (AR2Slow), and heterozygous ADAR2(flox/+)/VAChT-Cre.Fast (AR2H) mice. The conditional ADAR2-knockout mice were divided into 3 groups by stage: presymptomatic (AR2H mice), early symptomatic (AR2 mice, AR2H mice) and late symptomatic (AR2Slow mice). Light-microscopically, some motor neurons in AR2 and AR2H mice (presymptomatic) showed simple neuronal atrophy and astrogliosis, and AR2H (early symptomatic) and AR2Slow mice often showed vacuoles predominantly in motor neurons. The number of vacuole-bearing anterior horn neurons decreased with the loss of anterior horn neurons in AR2H mice after 40 weeks of age. Electron-microscopically, in AR2 mice, while the cytoplasm of normal-looking motor neurons was almost always normal-appearing, the interior of dendrites was frequently loose and disorganized. In AR2H and AR2Slow mice, large vacuoles without a limiting membrane were observed in the anterior horns, preferentially in the nuclei of motor neurons, astrocytes and oligodendrocytes. Nuclear vacuoles were not observed in AR2res (ADAR2(flox/flox)/VAChT-Cre.Fast/GluR-B(R/R)) mice, in which motor neurons express edited GluA2 in the absence of ADAR2. These findings suggest that ADAR2-reduction is associated with progressive deterioration of nuclear architecture, resulting in vacuolated nuclei due to a Ca(2+)-permeable AMPA receptor-mediated mechanism.

Trehalose protects against spinal cord ischemia in rabbits.

OBJECTIVE: This study tested to see if trehalose, a cytoprotective disaccharide, protects against spinal cord ischemia in a rabbit model. METHODS: The infrarenal aorta was mobilized in four groups of 10 rabbits. In groups I, II, and III, it was clamped proximally and distally for 20 minutes. In group I, the clamped aorta was infused at 2.5 L/min for 2 hours with lactated Ringer's (LR) solution. In group II, the clamped aorta was infused with 5% trehalose in LR. LR was administered intravenously (2.0 mL/min) in groups I and II starting 30 minutes before clamping. In group III, 5% trehalose in LR was infused intravenously only. Group IV was a sham-operated control group without aortic clamping. At 8, 24, and 48 hours after reperfusion, hind limb function was scored using the Tarlov score (paralysis = 0, perceptible joint movement = 1, good joint movement but unable to stand = 2, able to walk = 3, normal = 4). Histologic analysis and electron microscopy were performed on anterior horn cells. RESULTS: The Tarlov scores in groups I, II, and III were, respectively, 1.1 ± 1.4, 3.5 ± 0.5, and 2.9 ± 0.9 at 8 hours; 0.8 ± 1.2, 3.9 ± 0.3, and 2.9 ± 0.9 at 24 hours; and 0.6 ± 0.7, 3.9 ± 0.3, and 2.7 ± 0.9 at 48 hours after reperfusion. Group IV scores were normal (4 ± 0) at all assessments. These scores were higher in groups II and III than in group I (P < .01) at all assessments. Scores at 24 and 48 hours were higher in group II than in group III (P < .05). In group III, delayed paraparesis developed in one rabbit at 24 hours and in two more at 48 hours. Histopathologic analysis showed the number of normal neurons was higher in groups II (P < .0001), III (P = .006), and IV (P < .0001) vs group I. Electron microscopy confirmed preserved neuronal cell ultrastructure in rabbits with normal limb function. CONCLUSIONS: Transaortic trehalose infusion was protective against paraplegia, whereas intravenous trehalose reduced spinal cord ischemia. This study was preliminary and further studies are needed.

Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury.

UNLABELLED: The present study examined the role of endogenous noradrenaline on glial and neuronal plasticity in the spinal cord in rats after peripheral nerve injury. An intrathecal injection of dopamine-ß-hydroxylase antibody conjugated to saporin (DßH-saporin) completely depleted noradrenergic axons in the spinal cord and also reduced noradrenergic neurons in the locus coeruleus (A6) and A5 noradrenergic nucleus in the brainstem and noradrenergic axons in the paraventricular nucleus of the hypothalamus. DßH-saporin treatment itself did not alter mechanical withdrawal threshold, but enhanced mechanical hypersensitivity and intrathecal clonidine analgesia after L5-L6 spinal nerve ligation. In the spinal dorsal horn of spinal nerve ligation rats, DßH-saporin treatment increased choline acetyltransferase immunoreactivity as well as immunoreactivity in microglia of ionized calcium binding adaptor molecule 1[IBA1] and in astrocytes of glial fibrillary acidic protein, and brain-derived nerve growth factor content. DßH-saporin treatment did not, however, alter the fractional release of acetylcholine from terminals by dexmedetomidine after nerve injury. These results suggest that endogenous tone of noradrenergic fibers is not necessary for the plasticity of α2-adrenoceptor analgesia and glial activation after nerve injury, but might play an inhibitory role on glial activation. PERSPECTIVE: This study demonstrates that endogenous noradrenaline modulates plasticity of glia and cholinergic neurons in the spinal cord after peripheral nerve injury and hence influences the pathophysiology of spinal cord changes associated with neuropathic pain.

High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats.

STUDY DESIGN: To examine the localization and expression of high-mobility group box-1 (HMGB-1) protein and its receptors after rat spinal cord injury. OBJECTIVE: To elucidate the contribution of HMGB-1 and its receptors as potential candidates in a specific upstream pathway to the proinflammatory response leading to a cascade of secondary tissue damage after spinal cord injury. SUMMARY OF BACKGROUND DATA: HMGB-1 was recently characterized as a key cytokine with a potential role in nucleosome formation and regulation of gene transcription. No studies have investigated the role of HMGB-1 in spinal cord injury. METHODS: Injured thoracic spinal cord from 62 rats aged 8 to 12 weeks and spinal cord from 20 control rats were examined. HMGB-1 was localized by immunofluorescence staining, costaining with cell markers, and by immunoelectron microscopy. The expression of HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, and TLR4 were also examined by immunohistochemistry. RESULTS: HMGB-1 expression appeared earlier than that of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in the spinal cord injury rats, with the HMGB-1 produced by both macrophages and neurons. HMGB-1 translocated from nucleus to cytoplasm in some neurons at an early stage after neural injury. Increased expression of HMGB-1, RAGE, and TLRs was observed after injury, and interaction of HMGB-1 with RAGE or TLRs, particularly in macrophage, was confirmed at 3 days after injury. CONCLUSION: Our results demonstrated an earlier onset in the expression of HMGB-1 than in tumor necrosis factor-α, IL-1ß, and IL-6 after spinal cord injury. The release of HMGB-1 from neurons and macrophages is mediated through the HMGB-1/RAGE or TLR pathways. HMGB-1 seems to play at least some roles in the proinflammatory cascade originating the secondary damage after the initial spinal cord injury.

Alterations in subcellular localization of TDP-43 immunoreactivity in the anterior horns in sporadic amyotrophic lateral sclerosis.

TDP-43 is ubiquitously expressed in the nucleus of motor neurons and is closely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). However, little is known about alterations in the subcellular or intracellular localization of TDP-43, either under normal conditions or in ALS. We examined the anterior horn neurons of the spinal cord in patients with sporadic ALS and age-matched controls immunohistochemically and immunoelectron-microscopically using anti-TDP-43 antibody. Immunohistochemically, the present study showed a decrease in TDP-43 immmunoreactivity in the nucleus and, by contrast, an increase in the cytoplasm in ALS patients. Immunoelectron-microscopically, we demonstrated the consistent presence of TDP-43-immunogold-labeled deposits primarily in the nucleus, particularly in the nucleolus, and frequently in the rough endoplasmic reticulum (rER), and, to a lesser extent, in the mitochondria and the synaptic vesicles of the presynaptic terminals on the surface of anterior horn neurons both in controls and ALS subjects. In ALS, a reduced number of TDP-43-immunogold-labeled deposits were observed in the nuclei, particularly in the nucleoli of even normal-looking motor neurons. In contrast, the number of TDP-43-immunogold-labeled deposits in the rER of the normal-appearing motor neurons was significantly larger in ALS than in the controls (p=0.0036). These findings suggest that TDP-43 is synthesized in the rER and translocates to the nucleus, particularly to the nucleolus, and in ALS, TDP-43 trafficking between the nucleus and the cytoplasm is disturbed, resulting in an accumulation of TDP-43 in the cytoplasm in the form of insoluble aggregates.

The evaluation of the influence of a high injury to brachial plexus elements on the condition of neurons of the anterior horns of the spinal cord--experimental research.

The aim of the experimental research was to assess the impact of a high damage to brachial plexus elements on the condition of neurons of spinal cord anterior horns. The research was conducted on 12 rabbits, in which the ventral branches of spinal nerves C5-Th1 were severed. During dissections carried out 7, 30, 60, 180 days after the operation the cervicothoracic segment of the spinal cord was collected. The material was subjected to microscopic histological and ultrastructural examinations, which showed that where brachial plexus elements had been severed some of the neurons of spinal cord anterior horns had died and that the process intensity depended on the time that had passed after the injury.

Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology.

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

[Experimental study on the functional reserve of ulnar nerve in rats].

OBJECTIVE: To study the functional change of nerve trunk after removing the partial bundles of ulnar nerve, to propose the concept of functional reserve of peripheral nerves and to investigate the functional reserve quantity of peripheral nerves. METHODS: Two hundred and twenty SD rats (male or female), aging 3 months and weighing 300-350 g, were randomized into the experimental group and the control group (n=110 per group). And the experimental group was subdivided into group 1/8, group 1/4, group 1/3, group 1/2 and group 2/3 according to the resection portion (n=22 per group). In the experimental group, the section of the lowest level on ulnar nerve trunks was exposed, and a certain portion of its bundles was separated and cut, while in the control group the bundles were only separated without resection. The general condition of all rats was observed, and the motoneurons in cornu anterius medullae spinalis were detected at 1 week, 2 weeks and 2 months after operation. The neuro-electrophysiology and the function of dominated muscles were detected at 2 weeks, 2 months, 3 months, and 4 months after operation. RESULTS: All the rats survived without infection and obvious ulcer in the limbs. The number of motoneurons in cornu anterius medullae spinalis in various experimental subgroups witnessed no obvious changes (P > 0.05). The superstructure changed obviously at the early postoperative stage in group 1/2 and group 2/3, but restored well at 2 months after operation. For the latent period of evoked potential, there was no significant difference between the various experimental subgroups and the control group at each time point (P > 0.05), but there was a significant difference among the various experimental subgroups when compared the time points of 2, 3 and 4 months to that of 2 weeks (P < 0.05) and no statistically significant difference at other time points (P > 0.05). For the wave amplitude of evoked potential of motor nerves, the maximum wave amplitude and the persistence time of the dominate muscle, there were significant differences between the various experimental subgroups and the control group at each time point (P < 0.05), and there were significant differences among the various experimental subgroups when comparing the time points of 2, 3 and 4 months to that of 2 weeks (P < 0.05) and no statistical significance at other time points (P > 0.05). CONCLUSION: The functional reserve of the ulnar nerve without compromise accounts the 1/3 of the whole trunk diameter.

Synapse involvement of the dorsal horn in experimental lumbar nerve root compression: a light and electron microscopic study.

STUDY DESIGN: This study was aimed at investigating changes in the dorsal horn of the lumbar cord induced by mechanical compression using an in vivo model. OBJECTIVE: To determine the effect of axonal flow disturbance in the dorsal horns induced by nerve root compression. SUMMARY OF BACKGROUND DATA: Few studies have looked at changes of synapses within the dorsal horn caused by disturbance of axonal flow and the axon reaction as a result of mechanical compression of the dorsal root. METHODS: In mongrel dogs, the 7th lumbar nerve root was compressed for 1 week, or 3 weeks using a clip. After intravenous injection of Evans blue albumin, they were observed under a fluorescence microscope for the purpose of clarifying the function of the blood-spinal cord barrier. Morphologic changes of the synapses in the dorsal horns secondary to the nerve fiber degeneration were examined by light and electron microscope. Changes on immuno-staining for substance P, calcitonin gene-related peptide, and somatostatin in the dorsal horn were also examined. RESULTS: Light microscope observation conducted 1 week after compression of the nerve roots revealed Wallerian degeneration of the myelinated nerve in the dorsal horn, and fluorescence microscope observation of these areas demonstrated edema formation resulting from damage of the blood-spinal cord barrier. Three weeks after the compression, electron microscope observation revealed shrinkage of the axon terminals, ubiquitous presence of high electron density degeneration and presence of synapses whose contact with synapses was disrupted. Immuno-histochemical studies showed a marked decrease of substance P, calcitonin gene-related peptide, and somatostatin staining in substance gelatinosa with Wallerian degeneration after compression of nerve root. CONCLUSION: It is important to recognize that compressive disturbance of the nerve roots caused Wallerian degeneration not only at the site of compression of nerve roots but also at the synapses of spinal cord dorsal horns.

Morphological features and responses to AMPA receptor-mediated excitotoxicity of mouse motor neurons: comparison in purified, mixed anterior horn or motor neuron/glia cocultures.

Primary motor neuron cultures are widely used as in vitro model to study the early mechanisms involved in the aetiology of amyotrophic lateral sclerosis. In this study, we directly compared the morphological features and the responses to AMPA receptor (AMPAR) activation of mouse spinal cord motor neurons under different culture conditions (OptiPrep-purified, mixed anterior horn or motor neuron/glia cocultures). Motor neurons cocultured with a confluent glial layer had significant improvements in axonal length and in somata perimeter and area, compared both to mixed anterior horn cultures and to purified cultures, suggesting that the presence of more "mature" glial cells was determinant to obtain healthier motor neurons. By immuno-cytochemical assays we found that both in mixed anterior horn cultures and in cocultures, lower AMPA (0.3 microM) or kainate (5 microM) concentrations, but not the higher (1 or 15 microM, respectively), induced classical apoptotic events such as the nuclear fragmentation, the membrane externalization of phosphatidylserine residues and the activation of caspases-9 and -3. The morphological features and the different degenerative pathways induced by AMPAR agonist concentrations suggest that the experimental conditions used for in vitro studies are key factors that should be deeply considered to obtain more valid and reproducible results.

Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS.

Recently, TAR DNA-binding protein of 43-kDa (TDP-43) was identified as a major component of ubiquitinated neuronal cytoplasmic inclusions observed in lower motor neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions. We herein investigated the relationship between TDP-43 immunoreactivities and fragmentation of the Golgi apparatus (GA). Each mirror section of spinal cord tissues in 10 ALS and 3 control cases were immunostained with polyclonal anti-TDP-43 and polyclonal anti-trans-Golgi-network (TGN)-46 antibodies. The neurons were divided into subtypes according to differences in TDP-43 immunoreactivities, and we examined the morphological changes of GA in each type. We divided the neurons into four subtypes according to the observed differences in TDP-43 immunoreactivities, Type A: neurons showing normal nuclear staining, Type B: neurons showing a loss of normal nuclear staining and a few granular cytoplasmic immunoreactivities, Type C: neurons showing a lot of granular immunoreactivities and no inclusions, Type D: neurons with inclusions. All of the neurons in Type A showed normal GA profiles, however, almost all of the neurons with abnormal TDP-43 immunoreactivities (Type B-D) showed GA fragmentation. These results suggest that neurons with abnormal TDP-43 immunoreactivities are associated with dysfunction of the secretory pathway in motor neurons.

Involvement of spinal motor neurons in parkin-positive autosomal recessive juvenile parkinsonism.

We intensively examined the spinal cord of an autosomal recessive juvenile parkinsonism (ARJP) female patient with a homozygous exon 3 deletion in the parkin gene, anticipating a possible involvement of anterior horn neurons. Although the clinical features of the patient were consistent with parkinsonism as a result of parkin mutation, her tendon reflex was abolished in the lower limbs. This feature was in contrast with hyperreflexia, usually found in previous reports of ARJP. Histologically, on the level of the cervical, thoracic, and sacral spinal cord, anterior horn neurons were well preserved and normal. However, the lumbar spinal cord exhibited many swellings of proximal axons (spheroids) and degenerative changes in the somata of the large anterior horn neurons such as central chromatolysis, cystatin C-negative small eosinophilic inclusions, and eosinophilic Lewy body-like inclusions. Ultrastructurally, accumulations of neurofilaments and abnormal structures, such as inclusion bodies similar to skein-like inclusions and disorganized rough endoplasmic reticulum, were observed in the somata and neuronal processes. Lewy body-like inclusions in this study were positively immunostained for both alpha-synuclein and ubiquitin that closely resemble Lewy bodies, but are different from Lewy body-like inclusions negatively immunostained for alpha-synuclein in amyotrophic lateral sclerosis. These findings suggest that eosinophilic inclusions that closely resemble Lewy bodies may be formed in the spinal motor neurons of ARJP patients with parkin mutations and the motor neurons of these patients may be vulnerable to neurodegeneration.

Induction of activating transcription factor 3 after different sciatic nerve injuries in adult rats.

Staining by activating transcription factor 3 (ATF3), a neuronal marker of nerve injury, was examined by immunocytochemistry in neurons and Schwann cells after crush or transection (regeneration inhibited) of rat sciatic nerve. ATF3 immunoreactivity peaked in neurons after three days and then gradually subsided to normal within 12 weeks after the crush. The response lasted somewhat longer and declined over time in spinal cord neurons but not in those of dorsal root ganglia (DRG) after transection, indicating a differential regulation of sensory and motor neurons. ATF3 expression was more pronounced in Schwann cells, and remained longer after transection, implying that to some extent regenerating axons produce signals that reduce ATF3 expression in Schwann cells. However, even after transection without repair (no contact with regenerating axons), ATF3 expression in Schwann cells in the distal segment decreased over time suggesting that regenerating axons are not entirely responsible for the down-regulation. These findings have clinical implications on when it is worthwhile to reconstruct nerve injuries.

Motor neuron involvement in experimental lumbar nerve root compression: a light and electron microscopic study.

STUDY DESIGN: The aim of this study is to investigate changes in lumbar motor neurons induced by mechanical nerve root compression using an in vivo model. This study is to investigate the changes of lumbar motor neuron induced by mechanical nerve root compression using in vivo model. OBJECTIVES: The effect of axonal flow disturbance induced by nerve root compression was determined in lumbar motor neuron. SUMMARY OF BACKGROUND DATA: The lumbar motor neuron should not be overlooked when considering the mechanism of weakness, so it is important to understand the morphologic and functional changes that occur in motor neurons of the spinal cord as a result of nerve root compression. However, few studies have looked at changes of neurons within the caused by disturbance of axonal flow, the axon reaction, chromatolysis, and cell death as a result of mechanical compression of the ventral root. METHODS: In mongrel dogs, the seventh lumbar nerve root was compressed for 1 week, or 3 weeks using a clip. Morphologic changes of the motor neurons secondary to the axon reaction were examined by light and electron microscopy. RESULTS: Light and electron microscopy showed central chromatolysis of motor neurons in the lumbar cord from 1 week after the start of compression. After 3 weeks, some neurons undergoing apoptosis were seen in the ventral horn. CONCLUSION: It is important to be aware that, in patients with nerve root compression due to lumbar disc herniation or lumbar canal stenosis, dysfunction is not confined to degeneration at the site of compression but also extends to the motor neurons within the lumbar cord as a result of the axon reaction. Patients with weakness of lower leg should therefore be fully informed of the fact that these symptoms will not resolve immediately after surgery.

Long descending motor tract axons and their control of neck and axial muscles.

It has been tacitly assumed that a long descending motor tract axon consists of a private line connecting the cell of origin to a single muscle, as a motoneuron innervates a single muscle. However, this notion of a long descending motor tract referred to as a private line is no longer tenable, since recent studies have showed that axons of all major long descending motor tracts send their axon collaterals to multiple spinal segments, suggesting that they may exert simultaneous influences on different groups of spinal interneurons and motoneurons of multiple muscles. The long descending motor systems are divided into two groups, the medial and the lateral systems including interneurons and motoneurons. In this chapter, we focus mainly on the medial system (vestibulospinal, reticulospinal and tectospinal systems) in relation to movement control of the neck, describe the intraspinal morphologies of single long descending motor tract axons that are stained with intracellular injection of horseradish peroxidase, and provide evidence that single long motor-tract neurons are implicated in the neural implementation of functional synergies for head movements.

Age-related changes in histogram pattern of anterior horn cells in human cervical spinal cord.

The purpose of the present study was to clarify age-related changes in histograms of spinal anterior horn cells. The study examined Rexed lamina IX of the C7 spinal cord segment in 22 men who had died of non-spinal disease (age range, 0-85 years). First, we confirmed that the size of nucleoli exhibited a linear relationship to the diameter of spinal anterior horn cells by preparing histograms of nucleoli. Second, this formula was used to create histograms of cervical anterior horn cells. Results were as follows: (i) diameter of nucleoli ranged from 2.0 microm to 6.0 microm; (ii) in each subject, no changes were seen in histogram patterns among ventral, intermediate, dorsal and overall sections; (iii) at < or =20 years of age, histograms displayed a single peak for the diameter of nucleoli at about 4.0-4.5 microm; (iv) at 21-60 years of age, histograms displayed two peaks, at about 3.5-4.0 microm and 5.0-5.5 microm; and (v) at 61-85 years of age, histograms displayed a single peak at about 5.0-5.5 microm.