Biology subjects

Schwarzschild, M. A.

Publications and source records attributed to Schwarzschild, M. A..

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

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↗

bioRxiv2024

LRRK2 G2019S mutation suppresses differentiation of Th9 and Treg cells via JAK/STAT3

The Leucine-rich repeat kinase-2 (LRRK2) G2019S mutation, resulting in aberrantly enhanced kinase activity, is one of the well-recognized genetic risk factors in Parkinsons Disease (PD). Increased LRRK2 activity was also observed in immune cells from PD patients. Emerging results have also unveiled an upsurge in -synuclein (-syn)-specific CD4+ T cell responses in PD patients. Given that LRRK2 mutations in PD are germline mutations, there are unmet meets to explore whether LRRK2 G2019S mutation contributes to the pathogenesis of PD via altering CD4+ T-cell functions. To fill this knowledge gap, we generated a new T cell receptor (TCR) transgenic mouse strain bearing LRRK2 G2019S knock-in mutation, OT-II/LRRK2 (Refer to Mut). As CD4+ T cells from OT-II mice specifically recognize ovalbumin, this new strain enables us to explore the impact of LRRK2 G2019S mutation on T-cell functions in an antigen-specific manner. We found that the abundance and proliferation of major immune subsets in spleen tissue from Mut mice are comparable to wild-type (OT-II, Refer to WT) control. However, when we characterized T cell differentiation in these two strains, T cells derived from Mut mice displayed increased Th2 differentiation (IL-4) and decreased Th9 (IL-9) and Treg (Foxp3+ %) differentiation. LRRK2 G2019S mutation significantly altered the expression levels of master transcription factors (TFs) for T cell differentiation. Specifically, Mut T cells displayed an increase in mRNA expression of Gata3 (TF for Th2), a decrease in expression of Irf4 and Foxp3 (TFs for Th9 and Treg, respectively). Mechanistically, LRRK2 mutation decreased IL-9 production and Treg cell population through the JAK/STAT3 signaling. In conclusion, LRRK2 plays a critical role in regulating T cell differentiation, warranting further studies to evaluate the impacts of altered T cell differentiation led by LRRK2 mutation in dopaminergic neuron damages.

immunology↗