Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. At present, no definite ALS biomarkers are available. In this study, exosomes from the plasma of patients with ALS and healthy controls were extracted, and differentially expressed exosomal proteins were compared. Among them, the expression of exosomal coronin-1a (CORO1A) was 5.3-fold higher than that in the controls. CORO1A increased with disease progression at a certain proportion in the plasma of patients with ALS and in the spinal cord of ALS mice. CORO1A was also overexpressed in NSC-34 motor neuron-like cells, and apoptosis, oxidative stress, and autophagic protein expression were evaluated. CORO1A overexpression resulted in increased apoptosis and oxidative stress, overactivated autophagy, and hindered the formation of autolysosomes. Moreover, CORO1A activated Ca²⁺-dependent phosphatase calcineurin, thereby blocking the fusion of autophagosomes and lysosomes. The inhibition of calcineurin activation by cyclosporin A reversed the damaged autolysosomes. In conclusion, the role of CORO1A in ALS pathogenesis was discovered, potentially affecting the disease onset and progression by blocking autophagic flux. Therefore, CORO1A might be a potential biomarker and therapeutic target for ALS.
Mice ; Animals ; Amyotrophic Lateral Sclerosis/pathology* ; Calcineurin/metabolism* ; Motor Neurons/pathology* ; Microfilament Proteins/metabolism* ; Cytoskeletal Proteins/metabolism*

BACKGROUND AND PURPOSE: Disruption of nucleoporins has been reported in the motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS). However, the precise changes in the morphology of nucleoporins associated with the pathology of the 43-kDa TAR DNA-binding protein (TDP-43) in the disease process remain unknown. We investigated the expression of nucleoporins that constitute the nuclear pore complex (NPC) in spinal motor neurons that exhibit sALS in relation to TDP-43 pathology, which is a reliable neuropathological hallmark of sALS. METHODS: Paraffin-embedded sections of the lumbar spinal cord were obtained for immunofluorescence analysis from seven control subjects and six sALS patients. Anti-TDP-43 antibody, anti-nucleoporin p62 (NUP62) antibody, and anti-karyopherin beta 1 (KPNB1) antibody were applied as primary antibodies, and then visualized using appropriate secondary antibodies. The sections were then examined under a fluorescence microscope. RESULTS: NUP62 and KPNB1 immunoreactivity appeared as a smooth round rim bordering the nuclear margin in normal spinal motor neurons that exhibited nuclear TDP-43 immunoreactivity. sALS spinal motor neurons with apparent TDP-43 mislocalization demonstrated irregular, disrupted nuclear staining for NUP62 or KPNB1. Some atrophic sALS spinal motor neurons with TDP-43 mislocalization presented no NUP62 immunoreactivity. CONCLUSIONS: Our findings suggest a close relationship between NPC alterations and TDP-43 pathology in the degenerative process of the motor neurons of sALS patients.
Amyotrophic Lateral Sclerosis* ; Antibodies ; Fluorescence ; Fluorescent Antibody Technique ; Humans ; Motor Neurons* ; Nuclear Pore ; Nuclear Pore Complex Proteins* ; Pathology ; Spinal Cord

Spinal cord injury (SCI), which is much in the public eye, is still a refractory disease compromising the well-being of both patients and society. In spite of there being many methods dealing with the lesion, there is still a deficiency in comprehensive strategies covering all facets of this damage. Further, we should also mention the structure called the corticospinal tract (CST) which plays a crucial role in the motor responses of organisms, and it will be the focal point of our attention. In this review, we discuss a variety of strategies targeting different dimensions following SCI and some treatments that are especially efficacious to the CST are emphasized. Over recent decades, researchers have developed many effective tactics involving five approaches: (1) tackle more extensive regions; (2) provide a regenerative microenvironment; (3) provide a glial microenvironment; (4) transplantation; and (5) other auxiliary methods, for instance, rehabilitation training and electrical stimulation. We review the basic knowledge on this disease and correlative treatments. In addition, some well-formulated perspectives and hypotheses have been delineated. We emphasize that such a multifaceted problem needs combinatorial approaches, and we analyze some discrepancies in past studies. Finally, for the future, we present numerous brand-new latent tactics which have great promise for curbing SCI.
Animals ; Astrocytes/cytology* ; Axons/physiology* ; Cell Transplantation ; Disease Models, Animal ; Electric Stimulation ; Humans ; Microglia/cytology* ; Motor Neurons/cytology* ; Nerve Regeneration ; Neuroglia/cytology* ; Neuronal Plasticity ; Neurons/cytology* ; Oligodendroglia/cytology* ; Pyramidal Tracts/pathology* ; Recovery of Function ; Regenerative Medicine/methods* ; Spinal Cord Injuries/therapy*

Previous studies have shown that electroacupuncture (EA) promotes recovery of motor function in Parkinson's disease (PD). However the mechanisms are not completely understood. Clinically, the subthalamic nucleus (STN) is a critical target for deep brain stimulation treatment of PD, and vesicular glutamate transporter 1 (VGluT1) plays an important role in the modulation of glutamate in the STN derived from the cortex. In this study, a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD was treated with 100 Hz EA for 4 weeks. Immunohistochemical analysis of tyrosine hydroxylase (TH) showed that EA treatment had no effect on TH expression in the ipsilateral striatum or substantia nigra pars compacta, though it alleviated several of the parkinsonian motor symptoms. Compared with the hemi-parkinsonian rats without EA treatment, the 100 Hz EA treatment significantly decreased apomorphine-induced rotation and increased the latency in the Rotarod test. Notably, the EA treatment reversed the 6-OHDA-induced down-regulation of VGluT1 in the STN. The results demonstrated that EA alleviated motor symptoms and up-regulated VGluT1 in the ipsilateral STN of hemi-parkinsonian rats, suggesting that up-regulation of VGluT1 in the STN may be related to the effects of EA on parkinsonian motor symptoms via restoration of function in the cortico-STN pathway.
Adrenergic Agents ; toxicity ; Animals ; Apomorphine ; pharmacology ; Disease Models, Animal ; Dopamine Agonists ; pharmacology ; Electroacupuncture ; methods ; Functional Laterality ; drug effects ; Male ; Medial Forebrain Bundle ; injuries ; Motor Activity ; drug effects ; physiology ; Neurons ; drug effects ; metabolism ; Oxidopamine ; toxicity ; Parkinson Disease, Secondary ; chemically induced ; physiopathology ; therapy ; Rats ; Rats, Sprague-Dawley ; Subthalamic Nucleus ; drug effects ; metabolism ; pathology ; Tyrosine 3-Monooxygenase ; metabolism ; Up-Regulation ; drug effects ; physiology ; Vesicular Glutamate Transport Protein 1 ; metabolism

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease that clinically manifests both upper and lower motor neuron signs. However, it is unknown where and how the motor neuron degeneration begins, and conflicting hypotheses have been suggested. Recent advanced radiological techniques enable us to look into ALS neuropathology in vivo. Herein, we report a case with upper motor neuron-predominant ALS in whom the results of brain magnetic resonance imaging (MRI) and myelin water fraction MRI suggest axonal degeneration.
Amyotrophic Lateral Sclerosis* ; Axons ; Brain ; Magnetic Resonance Imaging* ; Motor Neurons ; Myelin Sheath* ; Neuropathology ; Pathology ; Water*

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage. Muscle biopsy of propositus indicated a typical neurogenic amyotrophy. Genetic testing for SMA of mutation in SMN1 was negative, while for SBMA of androgen receptor showed the increased CAG repeat in exon 1, suggesting that although bulbar symptoms and androgen insensitivity are characteristic symptoms of SBMA, they are not obligatory for the diagnosis. In adult males with a chronic motor neuron syndrome without upper motor neuron signs, even in absence of the classical features of androgen insensitivity or bulbar findings, genetic testing for SBMA should be strongly considered.
Adult ; Bulbo-Spinal Atrophy, X-Linked ; complications ; diagnosis ; genetics ; Creatine Kinase ; blood ; Genetic Testing ; Humans ; Male ; Motor Neurons ; pathology ; Muscular Atrophy ; etiology ; Mutation ; genetics ; Paralysis ; diagnosis ; etiology ; Pedigree ; Receptors, Androgen ; genetics

ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.
Amyotrophic Lateral Sclerosis* ; Brain Stem ; Cell Line ; Humans ; Motor Neuron Disease ; Motor Neurons ; Pathology ; Prions ; Respiratory Insufficiency ; Spinal Cord

Approximately 15% of patients with frontotemporal dementia (FTD) have co-occurring motor neuron disease (MND). FTD-MND cases have frontotemporal lobar degeneration (FTLD)-transactive response DNA-binding protein (TDP) pathology, which is divided into four subtypes (types A, B, C, and D) based on the morphological appearance, cellular location, and distribution of the abnormal TDP inclusions and dystrophic neurites. We report a patient with FTD-MND whose pathological diagnosis was FTLD-TDP type B. This is the first documented autopsy-confirmed case of FTD-MND in Korea.
Autopsy* ; Diagnosis ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Humans ; Korea ; Motor Neuron Disease* ; Motor Neurons* ; Neurites ; Pathology

Approximately 15% of patients with frontotemporal dementia (FTD) have co-occurring motor neuron disease (MND). FTD-MND cases have frontotemporal lobar degeneration (FTLD)-transactive response DNA-binding protein (TDP) pathology, which is divided into four subtypes (types A, B, C, and D) based on the morphological appearance, cellular location, and distribution of the abnormal TDP inclusions and dystrophic neurites. We report a patient with FTD-MND whose pathological diagnosis was FTLD-TDP type B. This is the first documented autopsy-confirmed case of FTD-MND in Korea.
Autopsy* ; Diagnosis ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Humans ; Korea ; Motor Neuron Disease* ; Motor Neurons* ; Neurites ; Pathology

BACKGROUNDIn amyotrophic lateral sclerosis (ALS), repeater F waves are increased. Accurate assessment of repeater F waves requires an adequate sample size.

METHODSWe studied the F waves of left ulnar nerves in ALS patients. Based on the presence or absence of pyramidal signs in the left upper limb, the ALS patients were divided into two groups: One group with pyramidal signs designated as P group and the other without pyramidal signs designated as NP group. The Index repeating neurons (RN) and Index repeater F waves (Freps) were compared among the P, NP and control groups following 20 and 100 stimuli respectively. For each group, the Index RN and Index Freps obtained from 20 and 100 stimuli were compared.

RESULTSIn the P group, the Index RN (P = 0.004) and Index Freps (P = 0.001) obtained from 100 stimuli were significantly higher than from 20 stimuli. For F waves obtained from 20 stimuli, no significant differences were identified between the P and NP groups for Index RN (P = 0.052) and Index Freps (P = 0.079); The Index RN (P < 0.001) and Index Freps (P < 0.001) of the P group were significantly higher than the control group; The Index RN (P = 0.002) of the NP group was significantly higher than the control group. For F waves obtained from 100 stimuli, the Index RN (P < 0.001) and Index Freps (P < 0.001) of the P group were significantly higher than the NP group; The Index RN (P < 0.001) and Index Freps (P < 0.001) of the P and NP groups were significantly higher than the control group.

CONCLUSIONSIncreased repeater F waves reflect increased excitability of motor neuron pool and indicate upper motor neuron dysfunction in ALS. For an accurate evaluation of repeater F waves in ALS patients especially those with moderate to severe muscle atrophy, 100 stimuli would be required.

Adult ; Amyotrophic Lateral Sclerosis ; pathology ; physiopathology ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons ; physiology ; Neural Conduction ; physiology ; Sample Size