Biology subjects

Elhanafy, E.

Publications and source records attributed to Elhanafy, E..

4 recordsLinked to original sources

bioRxiv2026

NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease

Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel NaV1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective NaV1.7 blockade. Safinamide directly inhibited a NaV1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of NaV1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the NaV1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of NaV1.7 as a therapeutic target for Parkinsonian pain.

neuroscience↗

bioRxiv2024

Elucidating the Differential Impacts of Equivalent Gating-Charge Mutations in Voltage-Gated Sodium Channels

Voltage-gated sodium (Nav) channels are pivotal for cellular signaling and mutations in Nav channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function (GoF), loss-of-function (LoF) effects, or both. However, the mechanism behind this functional divergence of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino-acid substitutions at equivalent gating-charge positions in VSDI and VSDII of the cardiac sodium channel Nav1.5 show differential gating-property impacts in electrophysiology measurements. We conducted 120 {micro}s molecular dynamics (MD) simulations on wild-type and six mutants to elucidate the structural basis of their differential impacts. Our s-scale MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis elucidated how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study represents a significant leap forward in understanding structure- function relationships in Nav channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.

biophysics↗

bioRxiv2023

Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels

Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Nav genes, significantly surpassing the 60% phenotype (GoFo/LoFo) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork for targeted drug design in precision medicine.

biophysics↗

bioRxiv2018

Identification of meteorological factors affecting migration of wild birds into miyazaki and its relation to circulation of highly pathogenic avian influenza virus

Aim of our study is to establish models for predicting the number of migratory wild birds based on the meteorological data. From 136 species of wild birds, which have been observed at Futatsudate in Miyazaki, Japan, from 2008 to 2016, we selected the potential high-risk species, which can introduce highly pathogenic avian influenza (HPAI) virus into Miyazaki; we defined them as \"risky birds\". We then performed regression analysis to model the relationship between the number of risky birds and meteorological data. We selected 10 wild bird species as risky birds: Mallard (Anas platyrhynchos), Northern pintail (Anas acuta), Eurasian wigeon (Anas penelope), Eurasian teal (Anas crecca), Common pochard (Aythya ferina), Eurasian coot (Fulica atra), Northern shoveler (Anas clypeata), Common shelduck (Tadorna tadorna), Tufted duck (Aythya fuligula), and Herring gull (Larus argentatus). We succeeded in identifying five meteorological factors associated with their migration: station pressure, mean value of global solar radiation, minimum of daily maximum temperature, days with thundering, and days with daily hours of daylight under 0.1 h. We could establish some models for predicting the number of risky birds based only on the published meteorological data, without manual counting. Dynamics of migratory wild birds has relevance to the risk of HPAI outbreak, so our data could contribute to save the cost and time in strengthening preventive measures against the epidemics.

epidemiology↗