Biology subjects

Weigel, M. K.

Publications and source records attributed to Weigel, M. K..

3 recordsLinked to original sources

bioRxiv2026

FGF signaling induces disease-associated oligodendrocyte states and drives myelin pathology

Myelin integrity is essential for normal central nervous system (CNS) function and is disrupted in neuroinflammatory and neurodegenerative disorders, including multiple sclerosis and Alzheimer's disease. In these settings, myelin-forming oligodendrocytes adopt a conserved disease-associated transcriptional state, termed disease-associated oligodendrocytes (DAOs). How DAOs arise, the signals that drive their induction, and whether they actively contribute to pathology remain poorly understood. Here we show that FGF signaling instructs mature oligodendrocytes to enter disease-associated states that are sufficient to trigger myelin pathology. By screening disease-linked secreted factors, we identify FGF1 and FGF2 as potent inducers of a DAO-like state in purified oligodendrocyte cultures, characterized by transcriptional reprogramming and myelin-membrane shedding. In vivo, activating oligodendrocyte FGF signaling is sufficient to elicit DAO programs and myelin disruption, whereas inhibiting FGF signaling suppresses DAO induction in a mouse model of multiple sclerosis. Finally, analysis of post-mortem multiple sclerosis tissue reveals a concordant DAO-like state associated with increased engagement of the FGF/FGFR axis. Collectively, these studies define a regulated mechanism of DAO formation linked to myelin disruption and position mature oligodendrocytes as active contributors to myelin pathology in CNS disease.

neuroscience↗

bioRxiv2024

Nanobodies against the myelin enzyme CNPase as tools for structural and functional studies

2,3-cyclic nucleotide 3-phosphodiesterase (CNPase) is an abundant constituent of central nervous system non-compact myelin, frequently used as a marker antigen for myelinating cells. The catalytic activity of CNPase, the 3-hydrolysis of 2,3-cyclic nucleotides, is well characterised in vitro, but the in vivo function of CNPase remains unclear. CNPase interacts with the actin cytoskeleton to counteract the developmental closure of cytoplasmic channels that travel through compact myelin; its enzymatic activity may be involved in adenosine metabolism and RNA degradation. We developed a set of high-affinity nanobodies recognizing the phosphodiesterase domain of CNPase, and the crystal structures of each complex show that the five nanobodies have distinct epitopes. One of the nanobodies bound deep into the CNPase active site and acted as an inhibitor. Moreover, the nanobodies were characterised in imaging applications and as intrabodies, expressed in mammalian cells, such as primary oligodendrocytes. Fluorescently labelled nanobodies functioned in imaging of teased nerve fibers and whole brain tissue sections, as well as super-resolution microscopy. These anti-CNPase nanobodies provide new tools for structural and functional biology of myelination, including high-resolution imaging of nerve tissue.

biochemistry↗

bioRxiv2022

BMAL1 loss in oligodendroglial lineage cells dysregulates myelination and sleep

Myelination depends on maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that the dynamic nature of oligodendroglia and myelination are regulated by the circadian transcription factor BMAL1. Bmal1 knockdown in OPCs during development - but not adulthood - decreases OPC proliferation, whereas BMAL1 regulates OPC morphology throughout life. OPC-specific Bmal1 deficiency impairs remyelination in an age-dependent manner, suggesting that age-associated decrements in circadian regulation of oligodendroglia may contribute to the deficient remyelination potential in demyelinating diseases like multiple sclerosis (MS). This oligodendroglial dysregulation and dysmyelination increase sleep fragmentation in OPC-specific Bmal1 knockout mice, and sleep fragmentation is causally associated with MS. These findings have broad mechanistic and therapeutic implications for numerous brain disorders that include both myelin and sleep phenotypes. One-Sentence SummaryBMAL1 regulates the homeostatic maintenance of oligodendroglia and myelin, that subsequently controls sleep architecture.

neuroscience↗