Biology subjects

Schwartzentruber, A.

Publications and source records attributed to Schwartzentruber, A..

3 recordsLinked to original sources

bioRxiv2025

Secondary nucleation of α-Synuclein drives Mitochondria dysfunctions and Lewy body formation in Parkinson's Disease

The seeding of -Synuclein (Syn) is a key driver of Lewy pathology propagation in Parkinsons disease (PD) and forms the basis for recent diagnostic advances. However, it remains unclear how the structural and biochemical features of Syn seeds dictate their propagation efficiency, capacity to induce Lewy body formation, and resulting cellular toxicity. Using genetic and idiopathic PD cell models, we map the pathogenic cascade beginning with the seed-driven conversion of endogenous Syn, followed by impaired degradation, mitochondrial dysfunction, and ultimately Lewy body formation. By coupling kinetic modelling of aggregation with functional readouts, we identify secondary nucleation as the predominant mechanism generating toxic Syn aggregation intermediates, identifying the critical process that links seeding to pathology. Extending this framework to PD brain, we quantitatively correlate seeding capacity with the spatiotemporal spread and severity of Lewy pathology, revealing a mechanistic connection between Syn aggregation dynamics and disease progression at molecular, cellular, and anatomical levels. By unifying molecular mechanism with clinicopathological progression, our work identifies catalytic Syn fibrillar seeds as tractable targets for both disease-modifying therapy and biomarker development in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/676873v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@1eca299org.highwire.dtl.DTLVardef@a714d4org.highwire.dtl.DTLVardef@1486db5org.highwire.dtl.DTLVardef@1aa895_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISyn fibril-oligomer interplay drives mitochondrial abnormalities and Lewy pathology C_LIO_LIFibrillar Syn catalyse toxic aggregate formations via secondary nucleation C_LIO_LIPhosphorylated Syn evades lysosomal clearance and drives enhanced dysfunctions C_LIO_LISeeding capacity of Syn predicts Lewy pathology burden and disease progression C_LI

neuroscience↗

bioRxiv2020

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Background Mutations in parkin are the most common cause of early onset Parkinsons disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in parkin mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from parkin mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Methods Fibroblasts from 4 controls and 4 parkin mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Results Direct conversion of control and parkin mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Conclusions Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

neuroscience↗

bioRxiv2019

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation.

Mutations in LRRK2 are the most common cause of dominantly inherited Parkinsons disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of -synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein homeostasis, however how PD mutations in LRRK2 may lead to accumulation of ubiquitinated protein aggregates remains unclear. A main cellular pathway to remove aggregated ubiquitinated proteins is aggrephagy: the histone deacetylase HDAC6 recognizes ubiquitinated misfolded proteins and recruits them to the molecular motor cytoplasmic dynein which transports them to the perinuclear region where they are trapped in aggresomes that are subsequently removed by macroautophagy. Here we identified HDAC6 as a novel LRRK2 substrate and show that LRRK2 regulates HDAC6-dependent aggresome formation. LRRK2 directly interacted with the HDAC6 deacetylase domains via its Roc domain and phosphorylated HDAC6 on serine-22. Serine-22 phosphorylation of HDAC6 enhanced its interaction with cytoplasmic dynein and stimulated recruitment of ubiquitinated proteins to aggresomes. Knockdown or knockout of LRRK2 impaired HDAC6-mediated aggresome formation. PD mutant LRRK2 G2019S showed reduced interaction with HDAC6 and did not support aggresome formation to the same extend as wild type LRRK2. This was recapitulated in LRRK2 G2019S patient-derived iAstrocytes that showed an aggresome formation defect. In conclusion our data reveal HDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.

neuroscience↗