Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca²⁺ imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.
Humans ; Amyotrophic Lateral Sclerosis/therapy* ; Animals ; Axons/metabolism* ; Mitochondria/metabolism* ; Motor Neurons/pathology*

The functional role of glutamatergic (vGluT2) neurons in the pedunculopontine nucleus (PPN) in modulating motor activity remains controversial. Here, we demonstrated that the activity of vGluT2 neurons in the rostral PPN is correlated with locomotion and ipsilateral head-turning. Beyond these motor functions, we found that these rostral PPN-vGluT2 neurons remarkably respond to salient stimuli. Furthermore, we systematically traced the upstream and downstream projections of these neurons and identified two downstream projections from these neurons to the caudal pontine reticular nucleus/anterior gigantocellular reticular nucleus (PnC/GiA) and the zona incerta (ZI). Our findings indicate that the projections to the PnC/GiA inhibit movement, consistent with 'pause-and-play' behavior, whereas those to the ZI promote locomotion, and others respond to a new 'pause-switch-play' pattern. Collectively, these findings elucidate the multifaceted influence of the PPN on motor functions and provide a robust theoretical framework for understanding its physiological and potential therapeutic implications.
Pedunculopontine Tegmental Nucleus/physiology* ; Animals ; Neural Pathways/physiology* ; Vesicular Glutamate Transport Protein 2/metabolism* ; Locomotion/physiology* ; Glutamic Acid/metabolism* ; Neurons/physiology* ; Male ; Mice ; Motor Activity/physiology* ; Zona Incerta/physiology*

Motor neurons are an important type of neurons that control movement. The transgenic fluorescent protein (FP)-labeled motor neurons of zebrafish line is disadvantageous for studying the morphogenesis of motor neurons. For example, the individual motor neuron is indistinguishable in this transgenic line due to the high density of the motor neurons and the interlaced synapses. In order to optimize the in vivo imaging methods for the analysis of motor neurons, the present study was aimed to establish a microtubule-fluorescent fusion protein mosaic system that can label motor neurons in zebrafish. Firstly, the promotor of mnx1, which was highly expressed in the spinal cord motor neurons, was subcloned into pDestTol2pA2 construct combined with the GFP-α-Tubulin fusion protein sequence by Gateway cloning technique. Then the recombinant constructs were co-injected with transposase mRNA into the 4-8 cell zebrafish embryos. Confocal imaging analysis was performed at 72 hours post fertilization (hpf). The results showed that the GFP fusion protein was expressed in three different types of motor neurons, and individual motor neurons were mosaically labeled. Further, the present study analyzed the correlation between the injection dose and the number and distribution of the mosaically labeled neurons. Fifteen nanograms of the recombinant constructs were suggested as an appropriate injection dose. Also, the defects of the motor neuron caused by the down-regulation of insm1a and kif15 were verified with this system. These results indicate that our novel microtubule-fluorescent fusion protein mosaic system can efficiently label motor neurons in zebrafish, which provides a more effective model for exploring the development and morphogenesis of motor neurons. It may also help to decipher the mechanisms underlying motor neuron disease and can be potentially utilized in drug screening.
Animals ; Animals, Genetically Modified ; Green Fluorescent Proteins/pharmacology* ; Microtubules/metabolism* ; Motor Neurons ; Zebrafish/genetics* ; Zebrafish Proteins/genetics*

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*

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive disorder caused by a defect in the immunoglobulin mu binding protein 2 (IGHMBP2) gene, leading to motor neuron degeneration. We identified an infant with SMARD1 by targeted exome sequencing from a consanguineous Syrian family having a history of recurrent infant deaths. The patient initially presented intrauterine growth retardation, poor sucking, failure to thrive, and respiratory failure at the age of two months, and an inborn error of metabolism was suspected at first. Over a period of one month, the infant showed rapid progression of distal muscular weakness with hand and foot contractures, which were suggestive of neuromuscular disease. Using targeted exome sequencing, the mutation in IGHMBP2 was confirmed, although the first report was normal. Targeted exome sequencing enabled identification of the genetic cause of recurrent mysterious deaths in the consanguineous family. Additionally, it is suggested that a detailed phenotypic description and communication between bioinformaticians and clinicians is important to reduce false negative results in exome sequencing.
Carrier Proteins ; Contracture ; Exome ; Failure to Thrive ; Fetal Growth Retardation ; Foot ; Hand ; Humans ; Immunoglobulins ; Infant Death ; Infant ; Metabolism ; Motor Neurons ; Muscle Weakness ; Muscular Atrophy, Spinal ; Neuromuscular Diseases ; Respiratory Insufficiency

Spinal α-motoneurons directly innervate skeletal muscles and function as the final common path for movement and behavior. The processes that determine the excitability of motoneurons are critical for the execution of motor behavior. In fact, it has been noted that spinal motoneurons receive various neuromodulatory inputs, especially monoaminergic one. However, the roles of histamine and hypothalamic histaminergic innervation on spinal motoneurons and the underlying ionic mechanisms are still largely unknown. In the present study, by using the method of intracellular recording on rat spinal slices, we found that activation of either H or H receptor potentiated repetitive firing behavior and increased the excitability of spinal α-motoneurons. Both of blockage of K channels and activation of Na-Ca exchangers were involved in the H receptor-mediated excitation on spinal motoneurons, whereas the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were responsible for the H receptor-mediated excitation. The results suggest that, through switching functional status of ion channels and exchangers coupled to histamine receptors, histamine effectively biases the excitability of the spinal α-motoneurons. In this way, the hypothalamospinal histaminergic innervation may directly modulate final motor outputs and actively regulate spinal motor reflexes and motor execution.
Animals ; Histamine ; pharmacology ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; metabolism ; Motor Neurons ; drug effects ; physiology ; Rats ; Receptors, Histamine H2 ; metabolism ; Sodium-Calcium Exchanger ; metabolism

Animals ; Behavior, Animal ; physiology ; Dopamine ; metabolism ; Dopaminergic Neurons ; physiology ; Humans ; Mice ; Motor Activity ; physiology ; Parkinson Disease ; metabolism ; physiopathology ; Pars Compacta ; physiopathology

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

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.
Acetylcholine/metabolism ; Alzheimer Disease ; Animals ; Antibodies, Monoclonal/*pharmacology ; Basal Forebrain/*drug effects/metabolism ; Cholinergic Agents/administration & dosage/*pharmacology ; Cholinergic Neurons/*drug effects/metabolism ; Fluorodeoxyglucose F18 ; GABAergic Neurons/*drug effects/metabolism ; Glucose/*metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; Injections ; Maze Learning ; Motor Activity/physiology ; Positron-Emission Tomography ; Rats ; Ribosome Inactivating Proteins, Type 1/*pharmacology

OBJECTIVETo determine whether there are in vivo differences of metabolites levels in bilateral cortical masticatory area(CMA) of patients with sleep bruxism, compared with healthy controls using proton magnetic resonance spectroscopy(1H-MRS). Accordingly to explore if cortical control of the central jaw motor system is abnormal in sleep bruxism patients.

METHODSFifteen sleep bruxism patients and fifteen age- and gender-matched healthy controls underwent 1H-MRS of bilateral CMA using J-difference edited point-resolved spectroscopy sequence(MEGA-PRESS) technique. Levels of metabolites were quantified from the ratio of the metabolite integral to the unsuppressed water signal. Differences of levels of γ-aminobutyric acid(GABA), glutmate(Glu) and N-acetyl aspartate(NAA) in bilateral CMA between sleep bruxism patients and healthy controls were tested using two-way ANOVA.

RESULTSEdited spectra were successfully obtained from the bilateral CMA in all of the participants. Levels of GABA+, glutmate and NAA in right and left CMA in sleep bruxism patients were (2.45±0.48)×10(-3), (2.35±0.62)×10(-3), (10.65±1.84)×10(-3), (10.49±2.37)×10(-3), (10.70±3.61)×10(-3), and (11.26±4.01)×10(-3) respectively. In contrast, levels of GABA+, glutmate and NAA in right and left CMA in healthy controls were (2.63±0.68)×10(-3), (2.65±0.97)×10(-3), (11.19± 1.34)×10(-3), (10.58±3.14)×10(-3), (11.82±1.80)×10(-3), and (11.95±3.23)×10(-3). There were no differences in levels of GABA+(P=0.196), Glu(P=0.590), and NAA(P=0.292) between sleep bruxism patients and healthy controls, nor in inbilateral CMA(GABA+: P=0.837; Glu: P=0.510; NAA: P=0.628).

CONCLUSIONSThe results indicate the absence of any alteration of the cortical control of the central jaw motor system in the levels of GABA, Glu and NAA in patients with sleep bruxism.

Analysis of Variance ; Aspartic Acid ; analogs & derivatives ; analysis ; metabolism ; Case-Control Studies ; Glutamic Acid ; analysis ; metabolism ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; methods ; Masticatory Muscles ; metabolism ; physiopathology ; Motor Neurons ; metabolism ; Sleep Bruxism ; metabolism ; physiopathology ; gamma-Aminobutyric Acid ; analysis ; metabolism