Biology subjects

Helbing, D. L.

Publications and source records attributed to Helbing, D. L..

4 recordsLinked to original sources

bioRxiv2026

Convergent molecular signatures of ageing and injury in the peripheral nervous system

Peripheral nervous system (PNS) ageing is marked by structural and functional decline, yet it remains unclear whether ageing constitutes a distinct biological programme or reflects a chronic injury-like state. To address this, we performed an unbiased, comparative molecular analysis of PNS ageing, neuroprotective dietary restriction (DR), and nerve injury. We conducted transcriptomic and proteomic profiling of peripheral nerves from young, old and geriatric mice fed ad libitum or subjected to long-term DR, and proteomics of nerves collected at multiple time points following injury. Age-associated molecular changes followed both linear and non-linear trajectories, and DR partially attenuated these ageing-related alterations. Notably, ageing-and injury-induced proteomic signatures showed considerable similarities, supporting the concept that an aged nerve resembles an injured nerve. Together, our study provides the most comprehensive molecular resource of PNS changes during ageing, DR, and injury, enabling the definition of key molecular signatures underlying PNS physiology. All datasets are integrated into the "PNS-omics Viewer", a Shiny web application designed to facilitate data mining of the herein presented datasets (tba).

neuroscience↗

bioRxiv2025

Grey matter embedding of the cholinergic system

Integrity of acetylcholine-producing basal forebrain nuclei Ch1-4 is crucial for neurocognitive functioning and grey matter decline represents a hallmark of neuropsychiatric disorders, including Alzheimers disease, Parkinsons disease and schizophrenia. Approaches that link brain-wide grey matter atrophy with diminished cholinergic innervation from Ch1-4 projections are required for neuroimaging of disease stages and pharmacological decisions addressing cholinergic deficits. The current study assessed human magnetic resonance imaging-based markers for cholinergic nucleus subregions and synaptic targets in healthy exploration (HCP, n = 1113) and replication (IXI, n = 587) cohorts. Ch1-3 and Ch4 were delineated at 50% cytoarchitectonic probability to determine their grey matter coupling patterns using structural covariance analyses. Spatial colocalization with vesicular acetylcholine transporter, M1-muscarinic and 4{beta}2-nicotinic receptor density quantified the correspondence with synaptic cholinergic markers. All individual-level cholinergic nucleus and target region indices showed good test-retest reliability (R [≥] 0.80) when restricted to voxels with at least 10% grey matter probability. Spatial colocalization with presynaptic acetylcholine transporters emphasized a cholinergic nature of Ch1-4 grey matter and its coupling with corticopetal projections such as amygdala, insula and cingulate cortices. Subcortical gradients of M1-muscarinic receptor density and the Ch1-3 structural covariance map, however, dominated in locations of striatal cholinergic interneurons, such as nucleus accumbens, caudate nucleus and putamen. Ch4 covaried with medial thalamus and hippocampus, while both subregions structural covariance networks converged in a posterolateral Ch4 extensions, potentially resembling subputaminal nucleus of Ayala. The results emphasize Ch1-4 morphometry as marker for acetylcholine-driven brain regions and describe neuroimaging strategies to indicate synaptic cholinergic involvement. Significance StatementPrevious studies have suggested that grey matter alterations in basal forebrain Ch1-4 nuclei indicate cholinergic deficits in neurodegenerative and psychiatric pathologies. However, the use of Ch1-4 volume as a marker of cholinergic system integrity has yet to be validated. Additionally, there is a lack of non-invasive procedures to quantify integrity of regions innervated by its cholinergic projections. Our results suggest that grey matter coupling with Ch1-4 is a sensitive cholinergic system marker, mimicking the density distribution of synaptic cholinergic innervation. Furthermore, we introduce grey matter-based target region indices, evaluate their robustness in individual participants and describe regional contributions to M1-muscarinic, 4{beta}2-nicotinic and vesicular acetylcholine transporter gradients. The study advances our understanding of cholinergic circuits in vivo using magnetic resonance imaging.

neuroscience↗

bioRxiv2023

Proteomic analysis of peripheral nerve myelin during murine aging

Aging of the peripheral nervous system (PNS) is associated with structural and functional changes that lead to a reduction in regenerative capacity and the development of age-related peripheral neuropathy. Myelin is central to maintaining physiological peripheral nerve function and differences in myelin maintenance, degradation, formation and clearance have been suggested to contribute to age-related PNS changes. Recent proteomic studies have elucidated the complex composition of the total myelin proteome in health and its changes in neuropathy models. However, changes in the myelin proteome of peripheral nerves during aging have not been investigated. Here we show that the proteomes of myelin fractions isolated from young and old nerves show only subtle changes. In particular, we found that the three most abundant peripheral myelin proteins (MPZ, MBP and PRX) do not change in old myelin fractions. We also show a tendency for high-abundance myelin proteins other than these three to be downregulated, with only a small number of ribosome-related proteins significantly downregulated and extracellular matrix proteins such as collagens upregulated. In addition, we illustrate that the peripheral nerve myelin proteome reported in this study is suitable for assessing myelin degradation and renewal during peripheral nerve degeneration and regeneration. Our results suggest that the peripheral nerve myelin proteome is relatively stable and undergoes only subtle changes in composition during mouse aging. We proffer the resultant dataset as a resource and starting point for future studies aimed at investigating peripheral nerve myelin during aging. Said datasets are available in the PRIDE archive under the identifier PXD040719 (aging myelin proteome) and PXD041026 (sciatic nerve injury proteome).

neuroscience↗

bioRxiv2023

Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury

Preconditioning with LPS induces neuroprotection against subsequent cerebral ischemic injury, mainly involving innate immune pathways. Microglia are CNS-resident immune cells that respond early to danger signals through memory-like differential reprogramming. However, the cell-specific molecular mechanisms underlying preconditioning are not fully understood. To elucidate the distinct molecular mechanisms of preconditioning on microglia, we compared these cell-specific proteomic profiles in response to LPS preconditioning and without preconditioning and subsequent transient focal brain ischemia and reperfusion, - using an established mouse model of transient focal brain ischemia and reperfusion. A proteomic workflow, based on isolated microglia obtained from mouse brains by cell sorting and coupled to mass spectrometry for identification and quantification, was applied. Our data confirm that LPS preconditioning induces marked neuroprotection, as indicated by a significant reduction in brain infarct volume. The established brain cell separation method was suitable for obtaining an enriched microglial cell fraction for valid proteomic analysis. The results show a significant impact of LPS preconditioning on microglial proteome patterns by type I interferons, presumably driven by the interferon cluster regulator proteins Stat1/2.

neuroscience↗