Severe Motor Deficits Research Articles

Plasticity of premotor cortico-muscular coherence in severely impaired stroke patients with hand paralysis

Motor recovery in severely impaired stroke patients is often very limited. To refine therapeutic interventions for regaining motor control in this patient group, the functionally relevant mechanisms of neuronal plasticity need to be detected. Cortico-muscular coherence (CMC) may provide physiological and topographic insights to achieve this goal. Synchronizing limb movements to motor-related brain activation is hypothesized to reestablish cortico-motor control indexed by CMC.In the present study, right-handed, chronic stroke patients with right-hemispheric lesions and left hand paralysis participated in a four-week training for their left upper extremity. A brain-robot interface turned event-related beta-band desynchronization of the lesioned sensorimotor cortex during kinesthetic motor-imagery into the opening of the paralyzed hand by a robotic orthosis. Simultaneous MEG/EMG recordings and individual models from MRIs were used for CMC detection and source reconstruction of cortico-muscular connectivity to the affected finger extensors before and after the training program. The upper extremity-FMA of the patients improved significantly from 16.23 ± 6.79 to 19.52 ± 7.91 (p = 0.0015). All patients showed significantly increased CMC in the beta frequency-band, with a distributed, bi-hemispheric pattern and considerable inter-individual variability. The location of CMC changes was not correlated to the severity of the motor impairment, the motor improvement or the lesion volume. Group analysis of the cortical overlap revealed a common feature in all patients following the intervention: a significantly increased level of ipsilesional premotor CMC that extended from the superior to the middle and inferior frontal gyrus, along with a confined area of increased CMC in the contralesional premotor cortex.In conclusion, functionally relevant modulations of CMC can be detected in patients with long-term, severe motor deficits after a brain-robot assisted rehabilitation training. Premotor beta-band CMC may serve as a biomarker and therapeutic target for novel treatment approaches in this patient group.

PP103 Characteristics Of Systems Applied To Language Rehabilitation

INTRODUCTION:In Paraguay the main cause of Traumatic Brain Injury are the accidents in ground transportation. According to data from the Basic Health Indicators 2013 of the Ministry of Public Health and Social Welfare, the regions with the highest rate of accidents in ground transportation are located in the rural zone of the country. Linguistic or communication disorder, attention and memory are the first functions that must be rehabilitated. Is essential to improve the patient's language skills to intervene the other cognitive functions. The objective of this study is to determine if free augmentative communication systems have the characteristics necessary for the cognitive rehabilitation of the language to provide a low cost solution for Traumatic Brain Injury patients in rural areas of the country.METHODS:A list of seven characteristics that contributed to verbal comprehension and expression, reading and writing, logical-verbal reasoning and numeration and calculation were compiled and compared to the Gazespeaker, which is a free augmentative communication system.RESULTS:The Gazespeaker meets the seven characteristics required for language rehabilitation.CONCLUSIONS:For patients with Traumatic Brain Injury are required low cost tools and ease-to-use like the Gazespeaker. It is a good augmentative communication system which satisfies all the characteristics required for a good language rehabilitation. In addition, this free software allows the use of an eye tracking device that can be applied to patients with Traumatic Brain Injury and severe motor deficit.

A Bidirectional Brain-Machine Interface Featuring a Neuromorphic Hardware Decoder.

Bidirectional brain-machine interfaces (BMIs) establish a two-way direct communication link between the brain and the external world. A decoder translates recorded neural activity into motor commands and an encoder delivers sensory information collected from the environment directly to the brain creating a closed-loop system. These two modules are typically integrated in bulky external devices. However, the clinical support of patients with severe motor and sensory deficits requires compact, low-power, and fully implantable systems that can decode neural signals to control external devices. As a first step toward this goal, we developed a modular bidirectional BMI setup that uses a compact neuromorphic processor as a decoder. On this chip we implemented a network of spiking neurons built using its ultra-low-power mixed-signal analog/digital circuits. On-chip on-line spike-timing-dependent plasticity synapse circuits enabled the network to learn to decode neural signals recorded from the brain into motor outputs controlling the movements of an external device. The modularity of the BMI allowed us to tune the individual components of the setup without modifying the whole system. In this paper, we present the features of this modular BMI and describe how we configured the network of spiking neuron circuits to implement the decoder and to coordinate it with the encoder in an experimental BMI paradigm that connects bidirectionally the brain of an anesthetized rat with an external object. We show that the chip learned the decoding task correctly, allowing the interfaced brain to control the object's trajectories robustly. Based on our demonstration, we propose that neuromorphic technology is mature enough for the development of BMI modules that are sufficiently low-power and compact, while being highly computationally powerful and adaptive.

Closed-Loop Task Difficulty Adaptation during Virtual Reality Reach-to-Grasp Training Assisted with an Exoskeleton for Stroke Rehabilitation.

Stroke patients with severe motor deficits of the upper extremity may practice rehabilitation exercises with the assistance of a multi-joint exoskeleton. Although this technology enables intensive task-oriented training, it may also lead to slacking when the assistance is too supportive. Preserving the engagement of the patients while providing “assistance-as-needed” during the exercises, therefore remains an ongoing challenge. We applied a commercially available seven degree-of-freedom arm exoskeleton to provide passive gravity compensation during task-oriented training in a virtual environment. During this 4-week pilot study, five severely affected chronic stroke patients performed reach-to-grasp exercises resembling activities of daily living. The subjects received virtual reality feedback from their three-dimensional movements. The level of difficulty for the exercise was adjusted by a performance-dependent real-time adaptation algorithm. The goal of this algorithm was the automated improvement of the range of motion. In the course of 20 training and feedback sessions, this unsupervised adaptive training concept led to a progressive increase of the virtual training space (p < 0.001) in accordance with the subjects' abilities. This learning curve was paralleled by a concurrent improvement of real world kinematic parameters, i.e., range of motion (p = 0.008), accuracy of movement (p = 0.01), and movement velocity (p < 0.001). Notably, these kinematic gains were paralleled by motor improvements such as increased elbow movement (p = 0.001), grip force (p < 0.001), and upper extremity Fugl-Meyer-Assessment score from 14.3 ± 5 to 16.9 ± 6.1 (p = 0.026). Combining gravity-compensating assistance with adaptive closed-loop feedback in virtual reality provides customized rehabilitation environments for severely affected stroke patients. This approach may facilitate motor learning by progressively challenging the subject in accordance with the individual capacity for functional restoration. It might be necessary to apply concurrent restorative interventions to translate these improvements into relevant functional gains of severely motor impaired patients in activities of daily living.

Robotic Excision of Suture Entrapment of the Lumbosacral Trunk

Nerve injury is a rare but serious complication of sacrospinous apical suspension procedures, occurring in up to 2% of cases. Injury can occur to the pudendal nerve, lumbosacral trunk and sciatic nerve. Symptoms commonly include severe refractory pain, paresthesias and motor deficit.

A closed-loop BCI system for rehabilitation of the hemiplegic upper-limb: A performance study of the systems ability to detect intention of movement

Rehabilitation of the upper-limb by means of a brain computer interface (BCI) is based on detecting an “intention to act” in the brain and transforming this intention into actual movement by using a motorized orthesis. The visual and proprioceptive feedback that results from the systems’ generated movement following the subjects’ captured intention, is thought to close the sensori-motor loop. Closing the loop is a key feature of BCI-systems that is thought to induce cerebral plasticity and thereby facilitating rehabilitation. Ten chronic patients post-stroke with a severe upper-limb motor deficit and 10 healthy controls were included in the study. To mobilize wrist and finger movement, we used a pneumatic orthesis that was controlled by the BCI during a wrist flexion/extension task. The main objective was to evaluate the systems’ CPS capacity to “classify” the observed brain activation as either movement or rest. Activation was registered with a 27-channel g tec EEG during two series of 40 randomized trials (20 rest, 20 movements). The sample frequency was 256 Hz. The BCI classifier was capable to distinguish between movements and rest with comparable performance for patients and controls and equal levels of true positives and negatives (78% vs 77% for patients and 81% vs 80% for controls). The CSP classifier used a wide 8–30 Hz-frequency band filter to evaluate EEG activity. By cutting this large band into smaller sub-units, we showed that the systems’ performance could be optimized by using subject-specific smaller frequency bands. The pneumatic orthesis should be improved. The present closed-loop BCI-system for rehabilitation of the paretic upper-limb was well able to recognize intention of movement in the brain. Its practical interest for rehabilitation post-stroke needs to be confirmed by a longitudinal efficiency study.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

BackgroundThe mechanism underlying non-motor symptoms in Parkinson’s disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms.MethodsWe conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS) in 151 patients with early-stage Parkinson’s disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41) and low non-motor patients (LNM-PD).ResultsPatients in the HNM-PD group (n = 71) were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum.ConclusionsThis study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson’s disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.

Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration.

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and CNS degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL, and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL. Clinical-grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 was generated in a U.S. Food and Drug Administration-registered cGMP facility. AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration.

Closed-Loop Neuroprosthesis for Reach-to-Grasp Assistance: Combining Adaptive Multi-channel Neuromuscular Stimulation with a Multi-joint Arm Exoskeleton.

Stroke patients with severe motor deficits cannot execute task-oriented rehabilitation exercises with their affected upper extremity. Advanced rehabilitation technology may support them in performing such reach-to-grasp movements. The challenge is, however, to provide assistance as needed, while maintaining the participants' commitment during the exercises. In this feasibility study, we introduced a closed-loop neuroprosthesis for reach-to-grasp assistance which combines adaptive multi-channel neuromuscular stimulation with a multi-joint arm exoskeleton. Eighteen severely affected chronic stroke patients were assisted by a gravity-compensating, seven-degree-of-freedom exoskeleton which was attached to the paretic arm for performing reach-to-grasp exercises resembling activities of daily living in a virtual environment. During the exercises, adaptive electrical stimulation was applied to seven different muscles of the upper extremity in a performance-dependent way to enhance the task-oriented movement trajectory. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. Closed-loop neuromuscular stimulation could be well integrated into the exoskeleton-based training, and increased the task-related range of motion (p = 0.0004) and movement velocity (p = 0.015), while preserving accuracy. The highest relative stimulation intensity was required to facilitate the grasping function. The facilitated range of motion correlated with the upper extremity Fugl-Meyer Assessment score of the patients (p = 0.028). Combining adaptive multi-channel neuromuscular stimulation with antigravity assistance amplifies the residual motor capabilities of severely affected stroke patients during rehabilitation exercises and may thus provide a customized training environment for patient-tailored support while preserving the participants' engagement.

Neuropathological characterization of spinal motor neuron degeneration processes induced by acute and chronic excitotoxic stimulus in vivo

Motor neuron (MN) diseases are characterized by progressive cell degeneration, and excitotoxicity has been postulated as a causal factor. Using two experimental procedures for inducing excitotoxic spinal MN degeneration in vivo, by acute and chronic overactivation of α-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMPA) receptors, we characterized the time course of the neuropathological changes. Electron transmission microscopy showed that acute AMPA perfusion by microdialysis caused MN swelling 1.5h after surgery and lysis with membrane rupture as early as 3h; no cleaved caspase 3 was detected by immunochemistry. Chronic AMPA infusion by osmotic minipumps induced a slow degeneration process along 5days, characterized by progressive changes: endoplasmic reticulum swelling, vacuolization of cytoplasm, vacuole fusion and cell membrane rupture. Quantification of these ultrastructural alterations showed that the increase of vacuolated area was at the expense of the nuclear area. Caspase 3 cleavage was observed since the first day of AMPA infusion. We conclude that acute AMPA-induced excitotoxicity induces MN loss by necrosis, while the progress of degeneration induced by chronic infusion is slow, starting with an early apoptotic process followed by necrosis. In both the acute and chronic procedures a correlation could be established between the loss of MN by necrosis, but not by caspase 3-linked apoptosis, and severe motor deficits and hindlimb paralysis. Our findings are relevant for understanding the mechanisms of neuron death in degenerative diseases and thus for the design of pharmacological therapeutic strategies.

Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation.

Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml+ in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood-brain barrier, we used a mouse MLIV model to test the efficacy of bone marrow transplantation (BMT). We found that BMT suppressed the reduced myelination and the increased caspase-3 activity due to loss of TRPML1. Using a rotarod test, we demonstrated that early BMT greatly delayed the motor impairment in the mutant mice. These data offer the possibility that BMT might provide the first therapy for MLIV.

The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons.

Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN.

Does Contralesional Hand Function After Neonatal Stroke Only Depend on Lesion Characteristics?

In children having suffered from neonatal arterial ischemic stroke, the relationship between contralesional hand performance and structural changes in brain areas remote from the infarct site was examined. Using voxel-based morphometry, we correlated contralesional gross manual dexterity assessed by the box and block test and whole-brain gray and white-matter volume changes on high-resolution magnetic resonance imaging in 37 7-year-old post-neonatal arterial ischemic stroke children. We also compared the volume of the identified structures with magnetic resonance imaging data of 10 typically developing age-matched children. Areas showing the highest positive correlation with the box and block test scores were ipsilesional mediodorsal thalamus, contralesional cerebellar lobule VIIa Crus I, and ipsilesional corticospinal tract at the level of superior corona radiata, the posterior limb of the internal capsule, and the cerebral peduncle and the ipsilesional body of corpus callosum. When compared with typically developing age-matched children, post-neonatal arterial ischemic stroke children with severe contralesional hand motor deficit exhibited significant volume reductions in these structures (except the cerebellum), whereas no differences were found with those with good manual dexterity. No negative correlation was found between box and block test scores and brain areas. Contralesional hand performance after neonatal arterial ischemic stroke is correlated with atrophy in brain areas directly or functionally connected but anatomically remote from the infarct. Our study suggests a role of the cerebellar lobule VIIa Crus I and mediodorsal thalamus in manual dexterity. URL: https://clinicaltrials.gov. Unique identifier: NCT02511249.

A neurorobotic platform for locomotor prosthetic development in rats and mice

Objectives. We aimed to develop a robotic interface capable of providing finely-tuned, multidirectional trunk assistance adjusted in real-time during unconstrained locomotion in rats and mice. Approach. We interfaced a large-scale robotic structure actuated in four degrees of freedom to exchangeable attachment modules exhibiting selective compliance along distinct directions. This combination allowed high-precision force and torque control in multiple directions over a large workspace. We next designed a neurorobotic platform wherein real-time kinematics and physiological signals directly adjust robotic actuation and prosthetic actions. We tested the performance of this platform in both rats and mice with spinal cord injury. Main Results. Kinematic analyses showed that the robotic interface did not impede locomotor movements of lightweight mice that walked freely along paths with changing directions and height profiles. Personalized trunk assistance instantly enabled coordinated locomotion in mice and rats with severe hindlimb motor deficits. Closed-loop control of robotic actuation based on ongoing movement features enabled real-time control of electromyographic activity in anti-gravity muscles during locomotion. Significance. This neurorobotic platform will support the study of the mechanisms underlying the therapeutic effects of locomotor prosthetics and rehabilitation using high-resolution genetic tools in rodent models.

Devenir respiratoire à l’âge scolaire de la dysplasie bronchopulmonaire

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. The influence of its initial severity on long-term respiratory outcome remains uncertain.The purpose of this study was to examine the impact of "new BPD" on respiratory morbidity as well as respiratory function at rest and during exercise in school-age children.The 93 preterm newborns (<33 weeks gestation) presenting with BPD between 1997 and 2004 at the Rennes University Hospital had been proposed for a specific follow-up program. The children included in this cohort and presenting without severe handicap or motor deficit were eligible for this observational retrospective study. Their standardized clinical evaluation and the results of the pulmonary function tests and cardiopulmonary exercise tests performed between the ages of 7 and 14 years were studied. BPD was considered to be moderate when respiratory or oxygen support continued at 36 weeks gestation with an FiO2 less than 30% and severe when FiO2 was greater than 30%.Among the 36 children assessed, the initial severity of the BPD was mild in 12 cases, moderate in 12 cases, and severe in 12 cases. The mean age at the time of the pulmonary function test (PFT) was 9.9 (±1.9) years, 19 children (53%) had respiratory symptoms during the year before the test, and six (17%) underwent long-term treatment. The PFT was abnormal for 32 children (89%): 23 showed airway obstruction, 16 hyperinflation, three increases in bronchial reactivity, and two restrictions. The residual volume/total lung capacity ratio was the only parameter related to the severity of BPD (P<0.05). The cardiopulmonary exercise test was given to 35 children: 15 of them had normal exercise ability but with a limited ventilatory reserve.Half of the children included in this "new-BPD" follow-up cohort had clinical respiratory morbidity and most of the children followed presented with persistent alterations in pulmonary function tests at school age, which were not associated with significant alterations in the maximum aerobic performance.

Microdiscectomy for a Paracentral Lumbar Herniated Disk.

Lumbar disk herniations occur frequently and are often associated with leg pain, weakness, and paresthesias. Fortunately, the natural outcomes of radiculopathy due to a disk herniation are generally favorable, and the vast majority of patients improve with nonoperative care. Surgical intervention is reserved for patients who have significant pain that is refractory to at least 6 weeks of conservative care, patients who have a severe or progressive motor deficit, or patients who have any symptoms of bowel or bladder dysfunction. This paper reviews the preoperative and postoperative considerations, as well as the surgical technique, for a microdiscectomy for a lumbar intervertebral disk herniation.

Leukemia Inhibitory Factor Haplodeficiency Desynchronizes Glial Reactivity and Exacerbates Damage and Functional Deficits after a Concussive Brain Injury.

Reactions of both astrocytes and microglia to central nervous system injury can be beneficial or detrimental to recovery. To gain insights into the functional importance of gliosis, we developed a new model of adolescent closed-head injury (CHI) and interrogated the behavioral, physiological, and cellular outcomes after a concussive CHI in leukemia inhibitory factor (LIF) haplodeficient mice. These mice were chosen because LIF is important for astrocyte and microglial activation. Behaviorally, the LIF haplodeficient animals were equally impaired 4 h after the injury, but in the subsequent 2 weeks, the LIF haplodeficient mice acquired more severe motor and sensory deficits, compared with wild type mice. The prolonged accumulation of neurological impairment was accompanied by desynchronization of the gliotic response, increased cell death, axonal degeneration, diminished callosal compound action potential, and hypomyelination. Our results clearly show that LIF is an essential injury-induced cytokine that is required to prevent the propagation of secondary neurodegeneration.

Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations

Autosomal recessively inherited mutations in WNT1 were recently identified as a cause of severe osteogenesis imperfecta (OI).1–6 This finding does not address the critical role of Wnt1 in mid-hindbrain development...

Loss of VGLUT3 Produces Circadian-Dependent Hyperdopaminergia and Ameliorates Motor Dysfunction and l-Dopa-Mediated Dyskinesias in a Model of Parkinson's Disease

The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson's disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (∼70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. l-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson's disease and related disorders. Dopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson's disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson's disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to l-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson's disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson's disease and potentially other basal-ganglia-related disorders.

Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213.

Mysterin (also known as RNF213) is a huge intracellular protein with two AAA+ ATPase modules and a RING finger ubiquitin ligase domain. Mysterin was originally isolated as a significant risk factor for the cryptogenic cerebrovascular disorder moyamoya disease, and was found to be involved in physiological angiogenesis in zebrafish. However, the function and the physiological significance of mysterin in other than blood vessels remain largely unknown, although mysterin is ubiquitously expressed in animal tissues. In this study, we performed antisense-mediated suppression of a mysterin orthologue in zebrafish larvae and revealed that mysterin-deficient larvae showed significant reduction in fast myofibrils and immature projection of primary motoneurons, leading to severe motor deficits. Fast muscle-specific restoration of mysterin expression cancelled these phenotypes, and interestingly both AAA+ ATPase and ubiquitin ligase activities of mysterin were indispensable for proper fast muscle formation, demonstrating an essential role of mysterin and its enzymatic activities in the neuromuscular regulation in zebrafish.