Biology subjects

Oeckl, P.

Publications and source records attributed to Oeckl, P..

5 recordsLinked to original sources

bioRxiv2026

The huntingtin-HAP40 complex is a bidirectional cellular rheostat

Huntingtin-associated protein 40 (HAP40) is an obligate structural subunit of huntingtin (HTT) and is rapidly degraded when unbound, yet has been conserved across eukaryotes for over a billion years. Combining interactomics, quantitative respirometry, and transcriptomics, we show that the HTT-HAP40 complex functions as a bidirectional stoichiometric rheostat: unbuffered apo-HAP40 activates the Integrated Stress Response via ATF4 and DDIT3/CHOP, whereas unbuffered apo-HTT reciprocally drives cholesterol and fatty-acid biosynthesis through SREBF1/2. We identify the ER-mitochondria tether RMDN3 (PTPIP51) as a key HAP40 interactor, placing mitochondria-associated ER membranes (MAMs) at the rheostats convergence point, and demonstrate that HAP40 depletion specifically impairs respiratory complexes II/IV. Loss of rheostat balance reproduces transcriptional signatures of Huntingtons disease patient tissues, supporting a "dual failure" model in which collapse of stoichiometric buffering -- rather than aggregation toxicity alone -- drives pathogenesis. To our knowledge, this is the first obligate complex in which both unbound partners carry out distinct essential functions, defining stoichiometric buffering as a generalizable regulatory principle that couples complex assembly to metabolic and stress-response control across eukaryotes.

molecular biology↗

bioRxiv2025

Loss of FXR1 and FXR2 promotes accumulation of TDP-43 in aging-related stress granules

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 in vulnerable neurons may accompany the primary neuropathology of various neurodegenerative diseases, or represent the hallmark of others, such as amyotrophic lateral sclerosis. Aging is the major risk factor for neurodegeneration, and sufficient to induce accumulation of TDP-43 in chronic cytoplasmic stress granules possibly further maturing to irreversible aggregates. Reduced expression of Fragile X protein (FXP) family members (FMR1, FXR1 and FXR2) in vulnerable neurons is associated with neurodegeneration, and loss of each individual FXP induces overlapping and unique aging-related phenotypes in HAP1 and SH-SY5Y cell models. Therefore, we analyzed consequences of FXP loss on TDP-43 cytoplasmic mislocalization and stress granule formation in fibroblast-like HAP1 FXP knockout cells. FXP loss induced nuclear pore pathology, and passive egress of proteins and RNA was evident upon loss of FXR1 or FXR2. Cytoplasmic mislocalization of TDP-43 was restricted to FXR1 knockout cells upon impairment of nuclear import, and cytoplasmic TDP-43 induced spontaneous stress granules exclusively in FXR2 knockout cells. In contrast, loss of FMR1 had no effect on nucleocytoplasmic exchange or TDP-43. Hence, reduced expression of FXR1 and FXR2 in aging and neurodegeneration may contribute to TDP-43 pathology.

cell biology↗

bioRxiv2025

Molecular aging is the main driver of Parkinson's Disease

Aging as well as the presence of -synuclein (-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with -syn oligomers for the onset of PD symptoms remains unclear. Using an inducible -syn oligomer mouse model of PD, we demonstrate that the induction of PD associated -syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that -syn oligomer formation precedes motor decline in these aged mice, and age together with -syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of -syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the -syn model of PD.

neuroscience↗

bioRxiv2024

RIG-I mediated neuron-specific IFN type 1 signaling in FUS-ALS induces neurodegeneration and offers new biomarker-driven individualized treatment options for (FUS-)ALS

Recent research has demonstrated significant aberrant activation of the innate immune system in ALS model systems due to mutations in SOD1, TARDBP and C9orf72 through stimulation of the TBK1-IRF3 pathway. This pathway can be activated, for example, by cGAS-STING-dependent sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which have been identified as early pathology in FUS-ALS spinal motor neurons (sMNs). Therefore, we analysed innate immune pathways in isogenic and non-isogenic FUSmut iPSC-derived sMNs, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUSmut sMNs. Notably, we found evidence for accumulation of cytosolic dsRNA and its sensor RIG-I in FUS-ALS. RIG-I, but not MDA5, was found to be significantly upregulated in FUSmut sMNs, and siRNA-mediated knockdown abolished the increased IFN1 activation in FUSmut sMNs. In post-mortem analysis, RIG-I was highly expressed in the remaining -MNs. IFN treatment of FUSwt sMNs phenocopied the axonal degeneration of FUSmut sMNs. Mechanistically, DNA damage induction did not increase ISG expression, but dsRNA was increased in the mitochondria of FUSmut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. Furthermore, the JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analysed ISG expression in peripheral blood samples from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. Blood ISGs correlated with disease progression rate and negatively with disease duration. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualised biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paperRIG-I-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS

neuroscience↗

bioRxiv2024

Most L1CAM is not associated with extracellular vesicles in human biofluids and iPSC-derived neurons

Transmembrane L1 cell adhesion molecule (L1CAM) is widely used as a marker to enrich for neuron-derived extracellular vesicles (EVs), especially in plasma. However, this approach lacks sufficient robust validation. This study aimed to assess whether human biofluids are indeed enriched for EVs, particularly neuron-derived EVs, by L1CAM immunoaffinity, utilizing multiple sources (plasma, CSF, conditioned media from iPSC-derived neurons [iNCM]) and different methods (mass spectrometry [MS], nanoparticle tracking analysis [NTA]). Following a systematic multi-step validation approach, we confirmed isolation of generic EV populations using size-exclusion chromatography (SEC) and polymer-aided precipitation (PPT) - two most commonly applied EV isolation methods - from all sources. Neurofilament light (NfL) was detected in both CSF and blood-derived EVs, indicating their neuronal origin. However, L1CAM immunoprecipitation did not yield enrichment of L1CAM in EV fractions. Instead, it was predominantly found in its free-floating form. Additionally, MS-based proteomic analysis of CSF-derived EVs also did not show L1CAM enrichment. Our study validates EV isolation from diverse biofluid sources by several isolation approaches and confirms that some EV subpopulations in human biofluids are of neuronal origin. Thorough testing across multiple sources by different orthogonal methods, however, does not support L1CAM as a marker to reliably enrich for a specific subpopulation of EVs, particularly of neuronal origin.

neuroscience↗