A decline in the activities of oxidative phosphorylation (OXPHOS) complexes has been consistently reported in amyotrophic lateral sclerosis (ALS) patients and animal models of ALS, although the underlying molecular mechanisms are still elusive. Here, we report that receptor expression enhancing protein 1 (REEP1) acts as an important regulator of complex IV assembly, which is pivotal to preserving motor neurons in SOD1^G93A mice. We found the expression of REEP1 was greatly reduced in transgenic SOD1^G93A mice with ALS. Moreover, forced expression of REEP1 in the spinal cord extended the lifespan, decelerated symptom progression, and improved the motor performance of SOD1^G93A mice. The neuromuscular synaptic loss, gliosis, and even motor neuron loss in SOD1^G93A mice were alleviated by increased REEP1 through augmentation of mitochondrial function. Mechanistically, REEP1 associates with NDUFA4, and plays an important role in preserving the integrity of mitochondrial complex IV. Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.
Mice ; Animals ; Amyotrophic Lateral Sclerosis/metabolism* ; Superoxide Dismutase-1/metabolism* ; Superoxide Dismutase/metabolism* ; Mice, Transgenic ; Spinal Cord/pathology* ; Mitochondria/physiology* ; Disease Models, Animal

Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.
Amyotrophic Lateral Sclerosis/genetics* ; Animals ; Brain/pathology* ; Disease Models, Animal ; Gene Editing ; Neurodegenerative Diseases/pathology* ; Swine

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

BACKGROUND: It is important to determine prognostic factors for the outcome of amyotrophic lateral sclerosis (ALS) at an early stage. The time taken for symptoms to spread from spinal or bulbar regions to both (time to generalization; TTG) is considered a strong predictor of survival; however, this has rarely been studied in Asian populations. The aim of this retrospective study was to evaluate potential factors affecting prognosis in Chinese patients with sporadic ALS, with a focus on the association between TTG and overall survival. METHODS: Seventy-one patients with sporadic ALS who were hospitalized at Chinese PLA General Hospital from 2009 to 2016 were followed up until December 2017. Survival analysis was performed using univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards models. The clinical data of the patients were recorded and analyzed. Variables studied were age at symptom onset, sex, site of symptom onset, diagnostic latency, TTG, diagnostic category, ALS Functional Rating Scale-revised score, percent predicted forced vital capacity (FVC%), and disease progression rate (DPR) at diagnosis. RESULTS: The mean age at onset was 54 (SD = 10.2) years, and the median survival time from symptom onset was 41 months (95% confidence interval: 34-47). By univariate analysis, factors independently affecting survival were age at symptom onset (Log rank = 15.652, P < 0.0001), TTG (Log rank = 14.728, P < 0.0001), diagnostic latency (Log rank = 11.997, P = 0.001), and DPR (Log rank = 6.50, P = 0.011). In the Cox multivariate model, TTG had the strongest impact on survival time (hazard ratio = 0.926, P = 0.01). CONCLUSIONS TTG can be used as an effective indicator of prognosis in patients with sporadic ALS.
Adult ; Amyotrophic Lateral Sclerosis ; pathology ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Retrospective Studies

Extracellular vesicles (EVs), a heterogenous group of membrane-bound particles, are virtually secreted by all cells and play important roles in cell-cell communication. Loaded with proteins, mRNAs, non-coding RNAs and membrane lipids from their donor cells, these vesicles participate in normal physiological and pathogenic processes. In addition, these subcellular vesicles are implicated in the progression of neurodegenerative disorders. Accumulating evidence suggests that intercellular communication via EVs is responsible for the propagation of key pathogenic proteins involved in the pathogenesis of amyotrophic lateral sclerosis, Parkinson's diseases, Alzheimer's diseases and other neurodegenerative disorders. For therapeutic perspective, EVs present advantage over other synthetic drug delivery systems or cell therapy; ability to cross biological barriers including blood brain barrier (BBB), ability to modulate inflammation and immune responses, stability and longer biodistribution with lack of tumorigenicity. In this review, we summarized the current state of EV research in central nervous system in terms of their values in diagnosis, disease pathology and therapeutic applications.
Amyotrophic Lateral Sclerosis ; Blood-Brain Barrier ; Cell- and Tissue-Based Therapy ; Central Nervous System ; Diagnosis ; Drug Delivery Systems ; Extracellular Vesicles* ; Humans ; Inflammation ; Membrane Lipids ; Neurodegenerative Diseases* ; Pathology ; RNA, Messenger ; RNA, Untranslated ; Tissue Donors

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*

BACKGROUNDHigh expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics.

METHODSA total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed.

RESULTSAs compared with the NCs (201.64 [22.35-401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12-859.22] ng/ml, P< 0.05), and the patients with limb onset of disease (254.14 [69.12-859.22] ng/ml, P< 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77-334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20-404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32-859.22] ng/ml, P< 0.05) while no difference was found in the male patients (220.39 [69.12-748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037).

CONCLUSIONSPlasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.

Amyotrophic Lateral Sclerosis ; blood ; immunology ; pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Galectin 3 ; blood ; Humans ; Male ; Middle Aged ; Sex Factors ; Time Factors

BACKGROUNDAmyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders.

METHODSWe compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls.

RESULTSThe ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P < 0.001) than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (P < 0.001) and the HD patients (P < 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients (P = 0.004). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P < 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls (P = 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥4.5) were observed exclusively in the ALS patients.

CONCLUSIONSThe different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.

Action Potentials ; Adult ; Aged ; Amyotrophic Lateral Sclerosis ; pathology ; physiopathology ; Diagnosis, Differential ; Female ; Hand ; pathology ; Humans ; Male ; Middle Aged ; Muscle, Skeletal ; physiopathology ; Muscular Atrophy ; pathology ; physiopathology ; Retrospective Studies ; Spinal Muscular Atrophies of Childhood ; pathology ; Spondylosis ; pathology

Aged ; Agraphia ; etiology ; Amyotrophic Lateral Sclerosis ; complications ; pathology ; Female ; Frontotemporal Lobar Degeneration ; complications ; pathology ; Humans ; Magnetic Resonance Imaging