Motor Neuron Disease Research Articles

Comparing Outcomes of Per‐Oral Image‐Guided Gastrostomy With Radiologically Inserted Gastrostomy at a Quaternary Australian Hospital

ABSTRACTIntroductionPer‐oral Image‐guided gastrostomy (PIG) is an alternative to conventional radiologically inserted gastrostomy (RIG). PIG is less frequently used in Australia, despite a favourable complication profile reported within the literature. This case control study compares success and complication rates of these procedures at a quaternary Australian Hospital.MethodsRetrospective review of electronic medical records (EMR) was performed for patients undergoing radiological‐guided gastrostomy between January 2019 and January 2023. Clinical notes, operation reports, radiology reports and discharge summaries at the time and for subsequent readmissions within 3 months were reviewed. Outcomes measured included procedural indication, technical success rate, major and minor complications, readmission or death within 3 months.Results216 radiological guided gastrostomies were attempted (age 65.6 ± 12.6; range 20–93; 81 female and 135 male). Sixteen cases were abandoned prior to insertion. Gastrostomy was successful in 133/136 PIG (97.8%) and 63/64 RIG (98.4%). The most frequent indication for PIG was dysphagia secondary to Motor Neuron Disease (107/136) and for RIG was head and neck malignancy (41/64). There were significantly more major complications (15.6% vs. 6.6%, p = 0.043) and minor complications (14.0% vs. 2.9%, p = 0.003) with RIG compared to PIG. Tube malpositioning, leak/peritonitis, aspiration pneumonitis and tube dislodgement were significantly increased in RIG. There was no significant difference in readmission rate (5.1% for PIG vs. 9.4% for RIG) or mortality (2.2% vs. 7.8%).ConclusionCompared to conventional RIG, PIG showed a similar primary success rate and decreased incidence of both major and minor complications.

Chaperone dysfunction in motor neuron disease: new insights from studies of the SMN complex.

Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.

Comparing P300 flashing paradigms in online typing with language models.

The P300 Speller is a brain-computer interface system that allows victims of motor neuron diseases to regain the ability to communicate by typing characters into a computer by thought. Since the system has a relatively slow typing speed, different stimulus presentation paradigms have been proposed designed to allow users to input information faster by reducing the number of required stimuli or increase signal fidelity. This study compares the typing speeds of the Row-Column, Checkerboard, and Combinatorial Paradigms to examine how their performance compares in online and offline settings. When the different flashing patterns were tested in conjunction with other established optimization techniques such as language models and dynamic stopping, they did not make a significant impact on P300 speller performance. This result could indicate that further performance improvements on the system lie beyond optimizing flashing patterns.

Case report: Suspected propofol associated Heinz body anemia in five mechanically ventilated dogs: a historical case series

ObjectiveThe aim of this report is to raise awareness of the risk of oxidant-induced erythrocyte injury, including Heinz body (HB) anemia, in critically ill dogs by describing the condition in five dogs receiving constant rate infusions of propofol.Case summaryThis case series describes five dogs with suspected propofol-induced HB anemia undergoing mechanical ventilation (MV) for lower motor neuron disease. Four of the five dogs were treated for tick paralysis (Ixodes holocyclus) and one was treated for suspected eastern brown snake (Pseudonaja textilis) envenomation. Propofol constant rate infusions were administered as part of total intravenous anesthesia. All five dogs became anemic, and a complete blood count and blood smear interpretation by a specialist clinical pathologist confirmed the presence of oxidative red blood cell injury (eccentrocytosis and HBs). The duration of MV ranged from 76 to 131 h, with HBs identified within 47–96 h of commencing propofol. All five dogs survived to discharge, with one dog requiring a blood transfusion.DiscussionWhile propofol-induced HB anemia is a recognized phenomenon in cats, to the author’s knowledge, this is the first case series detailing multiple occurrences in dogs. Veterinarians should be aware of the risk of propofol-induced oxidative erythrocyte injury in dogs receiving prolonged infusions of propofol, and consider risk mitigation by using propofol as part of multiagent intravenous anesthesia, keeping dose rates as low as possible, and daily monitoring of blood smears and red blood cell indices.

Clinical features of FOSMN syndrome in Korea: A comparative analysis with bulbar-onset amyotrophic lateral sclerosis.

Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2% of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.

Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND

Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a commonly used outcome measure in clinical trials for motor neuron disease (MND) therapies. As such, understanding how differences in scores relate to patient perception of their disease status is important when interpreting ALSFRS-R data. Our study sought to estimate the minimal important difference (MID) for the ALSFRS-R, the smallest difference in scores at which patients perceive a change in their quality of life. Methods: Data were collected as part of a longitudinal, observational saliva management study, ProSec3. These included both the ALSFRS-R and a global rating of change question (GRoC), which asked participants to rate how their disease had progressed since the previous visit. Anchor-based and distribution-based methods have been used to estimate the MID of the ALSFRS-R. The MID was estimated using two methods of calculating the total ALSFRS-R score, the original summation scale method and the recently proposed interval scale method. Results: A total of 145 people with MND had longitudinal ALSFRS-R and GRoC data. Different methods estimated the ALSFRS-R MID to be in the range of 2.02–5.43 for the summation scale and 1.23–3.31 for the interval scale method over a 3-month period, the time between study visits. Using anchor-based methods our MID estimates for the ALSFRS-R are 3.8 points and 2 points, respectively. Conclusions: The results of this study can guide clinicians and researchers in the interpretation of ALSFRS-R data. However, further studies are required to more precisely estimate the ALSFRS-R MID.

Barriers and enablers encountered by bereaved informal motor neuron disease (MND) caregivers when trying to access bereavement support: a qualitative cross-sectional thematic analysis of semistructured interviews with 6–36 months postbereavement informal MND caregivers in the UK

BackgroundCaregivers of people with motor neuron disease (MND) face more negative consequences of caregiving than other terminal illnesses. The impact of this caregiver burden can negatively influence bereavement outcomes.ObjectivesThis study...

Cytoplasmic expression of trans-active response DNA-binding protein-43 in aged mice display hippocampal sclerosis-like degeneration and neuronal loss with reduced lifespan.

Trans-active response DNA-binding protein-43 (TDP-43) is the major pathological protein in motor neuron disease and TDP-43 pathology has been described in the brains of up to 50% of patients with Alzheimer disease (AD). Hippocampal sclerosis of aging (HS-A), an age-related neuropathology characterized by severe neuronal loss and gliosis in CA1 and/or subiculum, is found in ∼80% of cases that are positive for phosphorylated TDP-43. HS-A is seen as a co-pathology in cases with AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), and frontotemporal degeneration. To understand the pathogenetic relationships between HS-A and LATE-NC, mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus, alone or in an APP/PSEN1 background, were evaluated using histology, HALO software's object recognition algorithms, and protein expression assays. Twenty-four-month-old mice expressing cytosolic TDP-43 displayed marked neuronal loss and atrophy in the hippocampus, decreased β-amyloid plaque deposition and modulation of microglia and intermediate filament activation. TDP-43ΔNLS-expressing mice survived to only ∼24 months of age whether or not they had an APP/PSEN1 background. This HS-A-like model may provide insights into the pathogenesis of neurodegeneration seen in HS-A and in other TDP-43 proteinopathies.

Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss-of-function (LOF) causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, as well as RNA-seq data from blood and central nervous system tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing (WGS) with RNA-seq data. We further developed the Spliformer-motif model to identify splicing regulatory motifs. We analyzed Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analyzed WGS data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were employed to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor, or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired WGS/RNA-seq data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of WGS data from 1,370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA-seq), and TDP-43 LOF related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is critical for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif that accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.

Electrophysiological Abnormalities in Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease: Three New Patients and Review of the Literature.

Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients. We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients. These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles. The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.

Mood disorders in patients with motor neuron disease and frontotemporal symptoms: Validation of the Hospital Anxiety and Depression Scale for use in motor neuron disease.

Motor neuron disease (MND) is a heterogeneous neurodegenerative disorder, with nearly 50% of patients exhibiting cognitive and behavioral symptoms in addition to motor decline. Anxiety and depression, though frequently observed in this population, have been understudied in relation to motor and extra-motor profiles. Our study addresses this gap by validating the Hospital Anxiety and Depression Scale for Motor Neuron Disease (HADS-MND) and investigating the interplay between mood, clincial, and frontotemporal symptoms in a large sample of MND patients. A total of 249 MND patients underwent clinical, genetic, and neuropsychological assessments. The validity, reliability, sensitivity, and specificity of the HADS-MND global score and subscores were explored. Correlation analyses and group comparisons tested the link between mood, motor and extra-motor profiles. The bidirectional structure of the HADS-MND was confirmed, but receiver operating characteristics analysis suggests caution for clinical use of the anxiety and depression subscales. The global HADS-MND score is recommended as a measure of psychological distress, with a cut-off point of 10 detecting 38% of patients with altered scores. Moderate symptoms of anxiety and depression were present in 14% and 11% of cases, respectively. Depressive mood was higher in women, patients with frontotemporal symptoms, and severe motor-functional disabilities. Depressive and/or anxiety symptoms were linked to loneliness, behavioral changes, emotional dysregulation, and poor quality of life. Cognitive efficiency was not associated with mood. Mood disorders appeared independent of cognitive profiles but related to behavioral changes. This is particularly relevant for clinicians discussing end-of-life decisions with patients.

Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.

Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p<0.001, ANOVA, Tukey's post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients' quality of life.

Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.

Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.

Decoding speech intent from non-frontal cortical areas.

Brain-machine interfaces (BMIs) have advanced greatly in decoding speech signals originating from the speech motor cortices. Primarily, these BMIs target individuals with intact speech motor cortices but who are paralyzed by disrupted connections between frontal cortices and their articulators due to brainstem stroke or motor neuron diseases such as amyotrophic lateral sclerosis. A few studies have shown some information outside the speech motor cortices, such as in parietal and temporal lobes, that also may be useful for BMIs. The ability to use information from outside the frontal lobes could be useful not only for people with locked-in syndrome but also to people with frontal lobe damage, which can cause nonfluent aphasia or apraxia of speech. However, temporal and parietal lobes are predominantly involved in perceptive speech processing and comprehension. Therefore, to be able to use signals from these areas in a speech BMI, it is important to ascertain that they are related to production. Here, using intracranial recordings, we sought evidence for whether, when and where neural information related to speech intention could be found in the temporal and parietal cortices. Causal information enabled us to distinguish speech intent from resting state and other processes involved in language processing or working memory. Information related to speech intent was distributed widely across the temporal and parietal lobes, including superior temporal, medial temporal, angular, and supramarginal gyri. This provides evidence of a decodable production-related signal in these areas. This insight may help in designing speech brain-machine interfaces that could benefit people with locked-in syndrome, aphasia or apraxia of speech.

Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation

Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm3) when compared to controls (852 ± 77 mm3); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm3), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.

All Tongue Fasciculations are Not Motor Neuron Disease.

All Tongue Fasciculations are Not Motor Neuron Disease.

The role of vitamin E deficiency in equine neuromuscular disorders

Horses obtain vitamin E, an essential nutrient for neuromuscular health, through green pasture. Vitamin E dietary deficiencies can lead to neuromuscular diseases such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy, equine motor neuron disease and vitamin E deficient myopathy. Some horses are genetically susceptible to developing these neuromuscular diseases, but not all horses that are vitamin E deficient exhibit clinical signs. Vitamin E supplementation is effective at slowing or halting clinical signs of some of these diseases, but the neuromuscular damage is usually irreversible, except in the case of vitamin E deficient myopathy. Adequate access to vitamin E early in life is essential to preventing these conditions.

Motor Neuron Diseases and Central Nervous System Tractopathies: Clinical-Radiologic Correlation and Diagnostic Approach.

White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. ©RSNA, 2024 Supplemental material is available for this article.

Muscle-specific Bet1L knockdown induces neuromuscular denervation, motor neuron degeneration, and motor dysfunction in a rat model of familial ALS.

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Although ALS has historically been characterized as a motor neuron disease, there is evidence that motor neurons degenerate in a retrograde manner, beginning in the periphery at the neuromuscular junctions (NMJs) and skeletal muscle. We recently reported a vesicle trafficking protein Bet1L (Bet1 Golgi Vesicular Membrane Trafficking Protein Like) as a new molecule possibly linked to NMJ degeneration in ALS. In this study, we tested the hypothesis that Bet1L gene silencing in skeletal muscle could influence NMJ integrity, motor neuron function, and survival in a rat model of familial ALS (SOD1G93A transgenic). Small interfering RNA (siRNA) targeting the Bet1L gene was injected on a weekly basis into the hindlimb muscle of pre-symptomatic ALS and wild-type (WT) rats. After 3 weeks, intramuscular Bet1L siRNA injection significantly increased the number of denervated NMJs in the injected muscle. Bet1L knockdown decreased motor neuron size in the lumbar spinal cord, which innervated the siRNA-injected hindlimb. Impaired motor function was identified in the hindlimbs of Bet1L siRNA-injected rats. Notably, the effects of Bet1L knockdown on NMJ and motor neuron degeneration were more significant in ALS rats when compared to WT rats. Together, Bet1L knockdown induces denervation of NMJs, but also this knockdown accelerates the disease progression in ALS. Our results provide new evidence to support the potential roles of Bet1L as a key molecule in NMJ maintenance and ALS pathogenesis.

Mouse models for understanding physiological functions of ADARs.

Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS). Mouse models have played an important role in our current understanding of the physiology of ADAR proteins. With the advancement of genetic engineering technologies, a number of new mouse models have been recently generated, each providing additional insight into ADAR function. This review highlights both past and current mouse models, exploring the methodologies used in their generation, their respective discoveries, and the significance of these findings in relation to human ADAR physiology.