Biology subjects

Schmid, L.

Publications and source records attributed to Schmid, L..

4 recordsLinked to original sources

bioRxiv2026

The variability of reflex amplitude estimates in motor unit pools depends on the phenotype distribution and discharge statistics

Motor unit (MU) activity during electrically or mechanically evoked reflexes is used to examine the relationship between neural inputs and MU properties. However, variations in single-MU reflex amplitudes are not fully understood and limit their reliability in determining the input-output relation of motor neurons (MNs). Using experiments and computer simulations, we investigated (i) whether MN discharge statistics and muscle activation explain the variability of reflex amplitude estimates and (ii) whether these variations are reflected differently across distinct reflex amplitude estimation methods. We analyzed MU spike trains extracted from isometric contractions of the tibialis anterior muscle at 10 % and 20 % MVC (maximum voluntary contraction). Estimating reflex amplitudes based on the peristimulus frequencygram (PSF) at 10 % MVC, the linear regression between discharge rate (DR) and reflex amplitude was always positive, with p < 0.05 in 3 out of 6 subjects; however, the linear correlation was inconsistent at 20 % MVC. We thereby observed that inter-subject variability was associated with the coefficient of variation of the interspike intervals. Furthermore, the linear correlation between DR and peristimulus time histogram (PSTH) based reflex amplitudes was inconsistent for both contraction forces. To obtain further insights into the influence of MN properties, we simulated reflexes in a heterogeneous MN population using electrical circuit models and varied MN inputs. The simulations indicate that, besides mean input current and membrane noise, MN properties also contribute to the variability of reflex amplitude estimates. The MN heterogeneity is well captured by PSF-based reflex estimates but not by PSTH-based ones. These results show that variations in amplitude estimates of individual MU reflexes are due to complex interactions between intrinsic and extrinsic factors. As PSF-based reflex amplitude estimates reflect the MN size distribution, tracking PSF-based reflex amplitudes at fixed MVC levels across individual subjects could serve as a marker for investigating spinal adaptations under (patho)physiological conditions. Author summaryMotor neurons are specialized nerve cells that control human movement. Each motor neuron activates a specific set of muscle fibers, and the functional unit consisting of a motor neuron and muscle fibers is called a motor unit. We can observe the activity of motor neurons in humans by decomposing the electrical activity of muscles (the electromyogram) into contributions from individual motor units. Reflex responses of motor units are often used to study the input-output relation of motor neurons in humans. We used a combination of experiments and computer simulations to study the factors that influence the reflex amplitude of motor units during an excitatory reflex. We found that the reflex amplitude is non-linearly influenced by a number of intrinsic and extrinsic factors, e. g., motor neuron size, but also the muscle force. Additionally, we found that these factors have different effects on the results of the two common methods used to calculate the reflex amplitude. These results provide guidance on choosing a suitable evaluation method and on interpreting reflex experiments.

neuroscience↗

bioRxiv2025

Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1

Cellular responses to amino acid fluctuations often hinge on ubiquitin-mediated control of metabolic enzymes, yet the underlying E3 ligase pathways remain incompletely defined. Using quantitative proteomics and active cullin-RING ligase (CRL) profiling, we identify LRRC58 as a cysteine-responsive substrate receptor whose stability increases sharply under cysteine starvation. Proteomics reveals an inverse relationship between LRRC58 and the metabolic enzyme cysteine dioxygenase 1 (CDO1), suggesting a cysteine-linked regulatory axis. Biochemical reconstitution and cryo-EM structures show that LRRC58 forms an active CUL2-or CUL5-based CRL that selectively positions CDO1 for ubiquitylation at Lys8. By contrast, targeted protein degradation via the VHL-based CRL is achieved by recruitment of a distinct surface of CDO1, and more promiscuous ubiquitylation independent of Lys8. Together, our proteomics-guided discovery pipeline, cellular stability studies, and structural analyses uncover a metabolically-tuned LRRC58-CDO1 pathway that links cysteine availability to selective proteasomal turnover, reveals principles of metabolite-regulated CRL activity, and showcases mechanisms distinguishing endogenous and targeted protein degradation.

biochemistry↗

bioRxiv2023

Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: a simulation study

Postinhibitory excitation is a transient overshoot of a neurons baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneurons firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the strength of the postinhibitory excitation correlates with the amplitude of the inhibitory stimulus and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50 % of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition. Author SummaryHuman movement is determined by the activity of specialized nerve cells, the motoneurons. Each motoneuron activates a specific set of muscle fibers. The functional unit consisting of a neuron and muscle fibers is called a motor unit. The activity of motoneurons can be observed noninvasively in living humans by recording the electrical activity of the motor units using the electromyogram. We studied the behavior of human motor units in an inhibitory reflex pathway and found an unexpected response pattern: a rebound-like excitation following the inhibition. This has occasionally been reported for human motor units, but its origin has never been systematically studied. In non-human cells of the neural system, earlier studies reported that a specific membrane protein, the so-called h-channel, can cause postinhibitory excitation. In our study, we use a computational motoneuron model to investigate whether h-channels can cause postinhibitory excitation as observed in the experimental recordings. Using the model, we developed a method to detect features of h-channel activity in human recordings. Because we found these features in a half of the recorded motor units, we conclude that h-channels can facilitate postinhibitory excitation in human motoneurons.

neuroscience↗

bioRxiv2022

RUNX1 isoform disequilibrium in the development of trisomy 21 associated myeloid leukemia

Aneuploidy is a hallmark of cancer, but its complex nature limits our understanding of how it drives oncogenesis. Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia and is associated with markedly increased leukemia risk. Here, we propose that disequilibrium of the RUNX1 isoforms is key to the pathogenesis of trisomy 21 (i.e. Down syndrome)-associated myeloid leukemia (ML-DS). Hsa21-focused CRISPR-Cas9 screens uncovered a strong and specific RUNX1 dependency in ML-DS. Mechanistic studies revealed that excess of RUNX1A isoform - as seen in ML-DS patients - synergized with the pathognomonic Gata1s mutation in leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium or pharmacological interference with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidies, and opens new avenues for developing specific and targeted therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/483334v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@16c5a95org.highwire.dtl.DTLVardef@af0ec7org.highwire.dtl.DTLVardef@f36bcborg.highwire.dtl.DTLVardef@129e832_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗