Biology subjects

Eden, J.

Publications and source records attributed to Eden, J..

5 recordsLinked to original sources

bioRxiv2024

RABGAP1 acts as a sensor to facilitate sorting and processing of amyloid precursor protein

A key hallmark of Alzheimers disease (AD) is the accumulation of extracellular amyloid-{beta} plaques in the brains of patients. Amyloid-{beta} is a 40-42 amino acid peptide produced by the proteolytic processing of amyloid precursor protein (APP) by a series of membrane-bound proteases. APP is a type-I transmembrane protein and thus its trafficking to encounter the proteases represents a rate-limiting step in the progression of AD. Although there has been a focused research effort to understand APP processing, its trafficking itinerary and machinery is incompletely understood. To address this we have performed an unbiased interaction screen for interactors of the cytosolic tail of APP. We identified previously characterised APP binders, as well as novel interactors. We have mapped the binding of APP to multiple new machineries, including RABGAP1. We have demonstrated that RAB-GAP1 partially co-localises with APP and directly interacts with a YENPTY motif in the APP cytosolic tail. Depletion or overexpression of RABGAP1 caused mistrafficking and misprocessing of endogenous APP in both human and rodent neurons. Interestingly, this effect was dependent on the GAP activity of RABGAP1, demonstrating that RABGAP1 affects the trafficking of APP by modulating the RAB activity on endosomal subdomains. This novel trafficking mechanism has implications for other NPXY cargoes and also presents a possible therapeutic avenue to explore.

cell biology↗

bioRxiv2024

During haptic communication, the central nervous system compensates distinctly for delay and noise

Connected humans have been previously shown to exploit the exchange of haptic forces and tactile information to improve their performance in joint action tasks. As human interactions are increasingly mediated through robots and networks it is important to understand the impact that network features such as lag and noise may have on human behaviour. In this paper, we investigated the interaction with a human-like robot controller that provides similar haptic communication behaviour as human-human interaction and examined the influence and compensation mechanisms for delay and noise on haptic communication. The results of our experiments show that participants can distinguish between noise and delay, and make use of compensation mechanisms to preserve performance in both cases. However, while noise is compensated for by increasing co-contraction, delay compensation could not be explained by this strategy. Instead, computational modelling suggested that a feed-forward prediction mechanism is used to compensate for the temporal delay and yield an efficient haptic communication. Author summaryIncreasingly humans are making use of networks and robots to coordinate haptic interactions through teleoperation. However, with networks comes delays and noise that can change both the force that is transmitted and how we perceive that force. The haptic communication involved in joint actions, such as moving a piano or performing a pair spin, has been shown to improve performance, but how does delay affect this behaviour? We tested how participants tracked a moving target with their right hand when connected to a human-like robotic partner, when perturbed by delay or noise. Through a comparison between noise and delay perturbation in experimental performance and in simulation with a computational model, we found that participants could from small values of perturbation identify if the perturbation was from delay or noise and that they adopted different compensation strategies in each case.

neuroscience↗

bioRxiv2024

A quantitative pipeline to assess secretion of human leptin coding variants reveals mechanisms underlying leptin deficiencies

The hormone leptin, primarily secreted by adipocytes, plays a crucial role in regulating whole-body energy homeostasis. Homozygous loss-of-function mutations in the leptin gene (LEP) cause hyperphagia and severe obesity, primarily through alterations in leptins affinity for its receptor or changes in serum leptin concentrations. Although serum concentrations are influenced by various factors (e.g., gene expression, protein synthesis, stability in the serum), proper delivery of leptin from its site of synthesis in the endoplasmic reticulum via the secretory pathway to the extracellular serum is a critical step. However, the regulatory mechanisms and specific machinery involved in this trafficking route, particularly in the context of human LEP mutations, remain largely unexplored. We have employed the Retention Using Selective Hooks (RUSH) system to elucidate the secretory pathway of leptin. We have refined this system into a medium-throughput assay for examining the pathophysiology of a range of obesity-associated LEP variants. Our results reveal that leptin follows the default secretory pathway, with no additional regulatory steps identified prior to secretion. Through screening of leptin variants, we identified three mutations that lead to proteasomal degradation of leptin and one mutant that significantly decreased leptin secretion, likely through aberrant disulfide bond formation. These observations have identified novel pathogenic effects of leptin variants, which can be informative for therapeutics and diagnostics. Finally, our novel quantitative screening platform can be adapted for other secreted proteins.

cell biology↗

bioRxiv2023

Control limitations in the null-space of the wrist muscle system

The redundancy present within the musculoskeletal system may offer a non-invasive source of signals for movement augmen tation, where the muscle-to-force null-space could be controlled simultaneously to the natural limbs. Here, we investigated the viability of extracting movement augmentation control signals from the muscles of the wrist complex. Our study assessed i) if controlled variation of the muscle activation patterns in the wrist joints null-space is possible; and ii) whether force and null-space targets could be reached simultaneously. During the null-space target reaching condition, participants used EMG-to-force null-space muscle activation to move their cursor towards a displayed target while minimising the exerted force as visualised through the cursors size. Initial targets were positioned to require natural co-contraction in the null-space and if participants showed a consistent ability to reach for their current target, they would rotate 5{degrees} incrementally to generate muscle activation patterns further away from their natural co-contraction. In contrast, during the concurrent target reaching condition participants were required to match a target position and size, where their cursor position was instead controlled by their exerted flexion-extension and radial-ulnar deviation, while its size was changed by their natural co-contraction magnitude. The results collected from 10 participants suggest that while there was variation in each participants co-contraction behaviour, most did not possess the ability to control this variation for muscle-to-force null-space reaching. In contrast, participants did show a direction and target size dependent ability to vary isometric force and co-contraction activity concurrently. Our results show the limitations of using null-space activity in joints with a low level of redundancy.

neuroscience↗

bioRxiv2021

The control and training of single motor units in isometric tasks are constrained by a common synaptic input signal

Recent developments in neural interfaces enable the real-time and non-invasive tracking of motor neuron spiking activity. Such novel interfaces provide a promising basis for human motor augmentation by extracting potential high-dimensional control signals directly from the human nervous system. However, it is unclear how flexibly humans can control the activity of individual motor neurones to effectively increase the number of degrees-of-freedom available to coordinate multiple effectors simultaneously. Here, we provided human subjects (N=7) with real-time feedback on the discharge patterns of pairs of motor units (MUs) innervating a single muscle (tibialis anterior) and encouraged them to independently control the MUs by tracking targets in a 2D space. Subjects learned control strategies to achieve the target-tracking task for various combinations of MUs. These strategies rarely corresponded to a volitional control of independent input signals to individual MUs. Conversely, MU activation was consistent with a common input to the MU pair, while individual activation of the MUs in the pair was predominantly achieved by alterations in de-recruitment order that could be explained with history-dependent changes in motor neuron excitability. These results suggest that flexible MU control based on independent synaptic inputs to single MUs is not a simple to learn control strategy.

neuroscience↗