Biology subjects

Gveric, D.

Publications and source records attributed to Gveric, D..

3 recordsLinked to original sources

bioRxiv2025

Olfactory proteomics reveals the capacity of the HDAC1 inhibitor pyroxamide to halt the α-synuclein preformed fibrils-induced damage in nasal epithelial, microglial and dopaminergic neuronal cell lines

Parkinsons disease (PD) is the second most common neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons originating in the substantia nigra (SN) pars compacta and projecting to other brain regions, giving rise to motor and non-motor symptoms. Despite significant progress in understanding the molecular and cellular disruptions associated with PD, there remains an unmet clinical need for effective therapies. In this study, proteomic analysis of the olfactory tract (OT) in controls with no known neurological history (n=17) and PD subjects (n=21) revealed Lewy body disease (LBD) stage-dependent proteostatic impairment, accompanied by progressive modulation of the alpha-synuclein (-syn) functional interactome. Differential OT omic profiles (OMS) were used in a computational drug repurposing approach, reveling the HDAC1 inhibitor pyroxamide as one of the top drug candidates with in silico potential to restore altered OMS. To explore the potential therapeutic effects of pyroxamide, in vitro assays were performed using -syn preformed fibrils (PFFs). Pyroxamide treatment reduced -syn PFFs-induced toxicity in olfactory epithelial, microglial and dopaminergic neuronal cell lines, producing a protective effect against hydrogen peroxide-induced damage exclusively in brain-derived cell types. These findings confirm the suitability of omics profiles in drug repurposing workflows against PD, offering valuable insights into the potential of HDAC1 inhibitors in the therapeutic pipeline of PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=54 SRC="FIGDIR/small/679944v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1e7a8e8org.highwire.dtl.DTLVardef@229c2org.highwire.dtl.DTLVardef@39f5corg.highwire.dtl.DTLVardef@1d35105_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Novel in situ seeding immunodetection assay uncovers neuronal-driven alpha-synuclein seeding in Parkinson's disease

Aggregates of alpha-synuclein (-syn) and tau propagate through template-induced misfolding in the brains of Parkinsons (PD) and Alzheimers disease (AD) patients. Prion-like seeding is crucial in disease initiation and progression and represents a major target for drug-modifying therapies. The detection of aggregated -syn and tau seeding activity with seeding amplification assays (SAAs) have remarkable diagnostic and research potential. However, current SAAs rely on bulk tissue homogenates or fluids, losing critical spatial and cellular resolution. Here, we report our novel in situ seeding immunodetection (isSID) assay that enables the visualization of -syn and tau seeding activities with unprecedented morphological detail in intact biological samples. Using the isSID assay, we confirm seeding activity in the pathological aggregates of PD and AD, among others, while uncovering neuron-driven -syn seeding events that precede the onset of clinical symptoms in PD. Our findings provide new fundamental insights into the pathogenesis underlying neurodegeneration and establish an invaluable tool for studying protein aggregation dynamics, with potential applications in biomarker discovery, diagnostics and drug testing.

neuroscience↗

bioRxiv2022

Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains

BackgroundDysregulation of microRNA (miRNA)-mediated gene expression has been implicated in the pathogenesis and course of many neurodegenerative diseases including Parkinsons disease (PD). However, the functionally relevant miRNAs remain largely unknown. Previous meta-analyses on differential miRNA expression data in post-mortem PD brains have highlighted several miRNAs showing consistent and statistically significant effects. However, these meta-analyses were based on exceedingly small sample sizes. MethodsIn this study, we quantified the expression of the four most compelling PD candidate miRNAs from these meta-analyses in the superior temporal gyrus (STG) of one of the largest case-control post-mortem brain datasets available (261 samples), thereby quadruplicating previously investigated sample sizes. Furthermore, we probed for common differential miRNA expression signatures with Alzheimers disease (AD) by also analyzing these miRNAs in post-mortem STG of 190 AD patients and controls and by testing six top AD miRNAs in the PD brains. ResultsOf all ten analyzed miRNAs, PD candidate miRNA homo sapiens (hsa-) miR-132-3p showed evidence for differential expression in both PD (p=4.89E-06) and AD (p=3.20E-24), and AD miRNAs hsa-miR-132-5p (p=4.52E-06) and hsa-miR-129-5p (p=0.0379) showed evidence for differential expression in PD. Combining these novel data with previously published data substantially improved the statistical support (=3.85E-03 using Bonferroni correction) of the corresponding meta-analyses clearly and compellingly implicating these miRNAs in both PD and AD. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with neuropathological Braak PD staging (p=3.51E-03/p=0.0117), suggesting that these miRNAs may play a role in -synuclein aggregation beyond the early disease phase. ConclusionsOur study represents the largest independent assessment of recently highlighted candidate brain miRNAs in PD and AD post-mortem brain samples, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both PD and AD brains, potentially pinpointing shared pathogenic mechanisms across these neurodegenerative diseases.

neuroscience↗