Biology subjects

Ueceyler, N.

Publications and source records attributed to Ueceyler, N..

3 recordsLinked to original sources

bioRxiv2025

Axon guidance deficits in a human sensory neuron model of Fabry disease

Fabry disease (FD) is a rare genetic galactosidase alpha (GLA) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health- related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic GLA knockout line (p.S364del, hemizygous) and its healthy control into sensory neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory model, with potential implications for early central and peripheral innervation in small fiber neuropathy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/673441v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@199cd19org.highwire.dtl.DTLVardef@682521org.highwire.dtl.DTLVardef@15da60borg.highwire.dtl.DTLVardef@1404c10_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Multi-omic characterization of human sural nerves acrosspolyneuropathies

Diseases of peripheral nerves termed polyneuropathies (PNPs) are common, mechanistically heterogeneous, and challenging to diagnose. Here, we integrated single nuclei transcriptomics of peripheral nerves from 33 human PNP patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics. We identified novel and human-specific nerve cell type markers including unexpectedly heterogeneous perineurial fibroblasts. All PNPs shared a loss of myelinating and an increase in repair Schwann cells and endoneurial lipid-associated macrophages. Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as pan-nerve diseases. Spatially, PNPs showed a previously unknown perineurial hyperplasia and fibrotic dispersion and this was most pronounced in immune-mediated PNPs. Single cell transcriptomics supported the differential diagnosis of PNPs with potential for future unbiased diagnostic classification. One-sentence summaryThe first large-scale integrated single cell and spatial transcriptomic characterization of human peripheral nerves identifies novel cell markers and unexpected heterogeneity of perineurial cells, reveals polyneuropathies as pan-nerve diseases, and shows that single cell transcriptomics hold potential for unbiased nerve disease classification.

neuroscience↗

bioRxiv2024

Proteomic analysis of isolated nerve terminals from NaV1.9 knockout mice reveals pathways relevant for neuropathic pain signalling

Neuropathic pain substantially affects the mental and physical well-being of patients and magnifies the socio-economic burden on the healthcare system. It is important to understand the molecular mechanisms underlying chronic pain to effectively target it. To investigate peripheral mechanisms relevant to pain signaling, we isolated nerve terminals from mouse footpads. The isolated peripheral terminals contain both pre- and post-synaptic proteins and are deficient in keratin and histone in both mice and humans. We detected the protein translational machinery and mitochondria in nerve terminals and observed that they were capable of endocytosis. An unbiased proteomic analysis of nerve terminals from footpads of NaV1.9 knockout mice shows dysregulation of the p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1/2 (ERK1/2) pathways, and of protein components involved in translation and energy metabolism. Isolation of human nerve terminals from skin punch biopsies, validated by proteomic analysis, highlights the broad and translational value of our approach. Our study thus reveals peripheral signaling mechanisms implicated in pain perception.

neuroscience↗