Biology subjects

Seidel, O.

Publications and source records attributed to Seidel, O..

3 recordsLinked to original sources

bioRxiv2025

1-Deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway

1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, but their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We first applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged 1-deoxysphingolipids in RPE-1 cells, observing that they are retained in the endoplasmic reticulum (ER). We found that 1-deoxysphingolipids can be transported by the non-vesicular transporter CERT in vitro but are retained at ER exit sites (ERES) in cells, suggesting that they do not efficiently sort into vesicular carriers. Cells expressing disease-associated variants of serine palmitoyl-CoA transferase (SPT) accumulated long-chain 1-deoxysphingolipids, which reduced ER membrane fluidity and enlarged ERES. We observed that the rates of membrane protein release from the ER were altered in response to mutant SPT expression, in a manner that was dependent on the cargo affinity for ordered or disordered membranes. We propose that dysregulation of sphingolipid metabolism alters secretory membrane properties, which can then modulate protein trafficking.

cell biology↗

bioRxiv2025

Abnormal Lipid Metabolism and Altered Neuronal Support by Astrocytes Lacking Akap11, a Risk Gene for Schizophrenia and Bipolar Disorder

A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3,5-cyclic AMP and protein kinase A (PKA) signaling. These metabolic perturbations manifested as increased lipid droplet accumulation in Akap11 mutant astrocytes, highlighting AKAP11s critical role in regulating intracellular lipid homeostasis. Mechanistically, AKAP11 functions as an autophagy receptor mediating PKA degradation and interacts with endoplasmic reticulum-resident proteins VAP-A and VAP-B through its FFAT motif, providing possible molecular insight into AKAP11s regulation of lipid metabolism. Co-culture experiments with mouse astrocytes and human induced pluripotent stem cell-derived neurons demonstrated that loss of Akap11 in astrocytes, relative to wild-type, increases excitatory neurotransmission and neuronal activity. Collectively, these findings link AKAP11-mediated lipid and synaptic dysregulation to psychiatric disease risk and highlight the potential role of astrocytes in these disorders.

cell biology↗

bioRxiv2024

Reduction of SynGAP-γ, disrupted splicing of Agap3, and oligodendrocyte deficits in Srrm2 mice, a genetic model of schizophrenia and neurodevelopmental disorder

Rare loss-of-function variants in SRRM2, which encodes a nuclear speckle scaffold and splicing factor, are associated with schizophrenia and neurodevelopmental disorders. How SRRM2 haploinsufficiency disrupts brain function is unknown. We find that Srrm2+/- mice exhibit (i) large-scale changes in gene expression in neuronal and glial cells, affecting DNA-binding-, synapse-, translation-, mitochondria-related pathways across multiple brain regions; (ii) alterations in splicing and/or abundance of multiple postsynaptic proteins, including reduction of the gamma isoform of SynGAP and elevation of its interactor, Agap3; and (iii) reduced oligodendrocyte proportions, particularly in striatum, accompanied by decreased expression of myelin-related mRNAs and proteins. Human iPSC-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects. Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired startle responses, and EEG recordings reveal reduced sleep spindles resembling humans with schizophrenia. Our findings identify specific synaptic changes, splicing dysregulation, and impaired myelination as mechanisms linking SRRM2 haploinsufficiency to neuropsychiatric disease.

neuroscience↗