Biology subjects

Schumacher, J. G.

Publications and source records attributed to Schumacher, J. G..

3 recordsLinked to original sources

bioRxiv2026

Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small molecule Parkin agonism

Parkin, an E3 ubiquitin ligase encoded by PARK2, plays a key role in both hereditary and sporadic Parkinsons disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological -synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with -synuclein preformed fibrils. Furthermore, FB231 attenuated -synuclein pathology and dopaminergic neurodegeneration in a gut -synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.

neuroscience↗

bioRxiv2025

AutoMorphoTrack: An Automated Python Package for Organelle Morphology, Motility, and Colocalization Analysis in Live-Cell Imaging

Quantitative imaging of organelle dynamics provides crucial insights into cellular function, state, and organization; however, existing analysis workflows often require advanced coding expertise and multiple software tools. AutoMorphoTrack is an open-source Python toolkit that automates organelle detection, morphology classification, motility tracking, and colocalization from multichannel fluorescence microscopy image stacks. The platform includes adaptive segmentation, organelle trajectory reconstruction, and pixel-level overlap quantification within a unified, reproducible framework that can be executed as an interactive Jupyter notebook, a modular Python package, or through AI-assisted natural-language commands. Each analysis step outputs publication-ready images, time-lapse videos, and standardized quantitative data tables. To complement the main pipeline, an accompanying script--AMTComparison.py--is provided to demonstrate how AutoMorphoTracks outputs can be extended for comparative analysis across individual neurons or experimental conditions. Together, these tools provide an accessible and framework for high-content, reproducible quantification of subcellular morphology, motility, and interactions at single-cell resolution. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/665650v5_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@103ecb0org.highwire.dtl.DTLVardef@a81b6forg.highwire.dtl.DTLVardef@a145fcorg.highwire.dtl.DTLVardef@1f9c27c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Soluble Immune Factor Profiles in Blood and CSF Associated with LRRK2 Mutations and Parkinson's Disease

Background and ObjectivesMutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are one of the most common genetic causes of Parkinsons disease (PD) and are linked to immune dysregulation in both the central nervous system and periphery. However, peripheral and central profiles of soluble immune factors associated with LRRK2 mutations and PD have not been comprehensively characterized. Using serum and CSF samples from the LRRK2 Cohort Consortium (LCC), this study aimed to probe a broad range of soluble immune biomarkers associated with LRRK2 mutations and PD. MethodsWe investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of LRRK2 mutation carriers and non-carriers, both with and without PD. A total of 65 cytokines, chemokines, growth factors, and soluble receptors were assessed by Luminex immunoassay. A multivariable robust linear model was used to determine levels associated with LRRK2 mutations and PD status, adjusting for age, sex, and sample cohort. Correlations were assessed using the Spearman correlation coefficient. LRRK2 G2019S knock-in mice were used to validate the associations identified in the LCC. ResultsIn this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with LRRK2 mutations. In particular, serum stromal cell-derived factor-1 alpha (SDF-1 alpha) levels, as supported by findings in LRRK2 G2019S knock-in mice, and tumor necrosis factor receptor II (TNF-RII) were significantly increased after multiple comparison adjustment. In contrast, LRRK2 mutations were associated with reduced soluble immune markers, including BAFF, CD40-Ligand, I-TAC, MIP-3 alpha, NGF beta, and IL-27 in CSF. Those with clinically diagnosed PD, with or without LRRK2 mutations, did not show strong signals in serum but reduced inflammatory analytes in CSF, including MIF, MMP-1, CD30, Tweak, and SDF-1 alpha. In addition, we found that the serum levels of these soluble immune factors display varied correlations with their corresponding CSF levels. DiscussionThis study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration.

neuroscience↗