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Neurobiology of Disease Jun 2024Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A...
Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.
PubMed: 38914173
DOI: 10.1016/j.nbd.2024.106576 -
Proceedings of the National Academy of... Jul 2024In the quest to model neuronal function amid gaps in physiological data, a promising strategy is to develop a normative theory that interprets neuronal physiology as...
In the quest to model neuronal function amid gaps in physiological data, a promising strategy is to develop a normative theory that interprets neuronal physiology as optimizing a computational objective. This study extends current normative models, which primarily optimize prediction, by conceptualizing neurons as optimal feedback controllers. We posit that neurons, especially those beyond early sensory areas, steer their environment toward a specific desired state through their output. This environment comprises both synaptically interlinked neurons and external motor sensory feedback loops, enabling neurons to evaluate the effectiveness of their control via synaptic feedback. To model neurons as biologically feasible controllers which implicitly identify loop dynamics, infer latent states, and optimize control we utilize the contemporary direct data-driven control (DD-DC) framework. Our DD-DC neuron model explains various neurophysiological phenomena: the shift from potentiation to depression in spike-timing-dependent plasticity with its asymmetry, the duration and adaptive nature of feedforward and feedback neuronal filters, the imprecision in spike generation under constant stimulation, and the characteristic operational variability and noise in the brain. Our model presents a significant departure from the traditional, feedforward, instant-response McCulloch-Pitts-Rosenblatt neuron, offering a modern, biologically informed fundamental unit for constructing neural networks.
Topics: Neurons; Models, Neurological; Humans; Neuronal Plasticity; Action Potentials; Animals
PubMed: 38913890
DOI: 10.1073/pnas.2311893121 -
PloS One 2024Motor issues are frequently observed accompanying core deficits in autism spectrum disorder (ASD). Impaired motor behavior has also been linked to cognitive and social...
Motor issues are frequently observed accompanying core deficits in autism spectrum disorder (ASD). Impaired motor behavior has also been linked to cognitive and social abnormalities, and problems with predictive ability have been suggested to play an important, possibly shared, part across all these domains. Brain imaging of sensory-motor behavior is a promising method for characterizing the neurobiological foundation for this proposed key trait. The present functional magnetic resonance imaging (fMRI) developmental study, involving children/youth with ASD, typically developing (TD) children/youth, and neurotypical adults, will investigate brain activations during execution and observation of a visually guided, goal-directed sequential (two-step) manual task. Neural processing related to both execution and observation of the task, as well as activation patterns during the preparation stage before execution/observation will be investigated. Main regions of interest include frontoparietal and occipitotemporal cortical areas, the human mirror neuron system (MNS), and the cerebellum.
Topics: Humans; Magnetic Resonance Imaging; Child; Brain; Male; Adolescent; Female; Adult; Brain Mapping; Autism Spectrum Disorder; Movement; Autistic Disorder; Young Adult; Psychomotor Performance; Mirror Neurons
PubMed: 38913636
DOI: 10.1371/journal.pone.0296225 -
Brain Communications 2024While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1...
While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.
PubMed: 38911266
DOI: 10.1093/braincomms/fcae202 -
Brain Stimulation Jun 2024Transcranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation...
BACKGROUND
Transcranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation (TMS). Immediate transcranial evoked potentials (i-TEPs) have been obscured by pulse and muscular artifacts. Thus, the TEP peaks that are commonly reported have latencies that are too long to be caused by direct excitation of cortical neurons.
METHODS
In 25 healthy individuals, we recorded i-TEPs evoked by a single biphasic TMS pulse targeting the primary motor hand area (M1) or parietal or midline control sites. Sampling EEG at 50 kHz enabled us to reduce the duration of the TMS pulse artifact to a few milliseconds, while minor adjustments of the TMS coil tilt or position enabled us to avoid cranial muscular twitches during the experiment.
RESULTS
We observed an early positive EEG deflection starting after approx. 2 ms followed by a series of superimposed peaks with an inter-peak interval of ∼1.1-1.4 ms in multiple electrodes surrounding the stimulated sensorimotor region. This multi-peak i-TEP response was only evoked by TMS of the M1 region and was modified by changes in stimulation intensity and current direction.
DISCUSSION
Single-pulse TMS of the M1 evokes an immediate local multi-peak response at the cortical site of stimulation. Our results suggest that the observed i-TEP patterns are genuine cortical responses evoked by TMS caused by synchronized excitation of pyramidal neurons in the targeted precentral cortex. This notion needs to be corroborated in future studies, including further investigations into the potential contribution of instrumental or physiological artifacts.
PubMed: 38909748
DOI: 10.1016/j.brs.2024.06.008 -
American Journal of Human Genetics Jun 2024The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A...
The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.
PubMed: 38908375
DOI: 10.1016/j.ajhg.2024.05.023 -
Acta Psychologica Jun 2024Engaging in chasing, where an actor actively pursues a target, is considered a crucial activity for the development of social skills. Previous studies have focused...
Engaging in chasing, where an actor actively pursues a target, is considered a crucial activity for the development of social skills. Previous studies have focused predominantly on understanding the neural correlates of chasing from an observer's perspective, but the neural mechanisms underlying the real-time implementation of chasing action remain poorly understood. To gain deeper insights into this phenomenon, the current study employed functional near-infrared spectroscopy (fNIRS) techniques and a novel interactive game. In this interactive game, participants (N = 29) were tasked to engage in chasing behavior by controlling an on-screen character using a gamepad, with the goal of catching a virtual partner. To specifically examine the brain activations associated with the interactive nature of chasing, we included two additional interactive actions: following action of following the path of a virtual partner and free action of moving without a specific pursuit goal. The results revealed that chasing and following actions elicited activation in a broad and overlapping network of brain regions, including the temporoparietal junction (TPJ), medial prefrontal cortex (mPFC), premotor cortex (PMC), primary somatosensory cortex (SI), and primary motor cortex (M1). Crucially, these regions were found to be modulated by the type of interaction, with greater activation and functional connectivity during the chasing interaction than during the following and free interactions. These findings suggested that both the MNS, encompassing regions such as the PMC, M1 and SI, and the mentalizing system (MS), involving the TPJ and mPFC, contribute to the execution of online chasing actions. Thus, the present study represents an initial step toward future investigations into the roles of MNS and MS in real-time chasing interactions.
PubMed: 38905953
DOI: 10.1016/j.actpsy.2024.104363 -
Frontiers in Neuroscience 2024Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.
PubMed: 38903602
DOI: 10.3389/fnins.2024.1422912 -
Frontiers in Psychology 2024Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS...
Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.
PubMed: 38903475
DOI: 10.3389/fpsyg.2024.1114811 -
BioRxiv : the Preprint Server For... May 2024Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the...
Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.
PubMed: 38903116
DOI: 10.1101/2024.05.15.594402