Biology subjects

Kamen, Y.

Publications and source records attributed to Kamen, Y..

3 recordsLinked to original sources

bioRxiv2026

Dying oligodendrocytes persist without mitochondria

Myelin is an insulating, multi-layered membrane that supports axonal integrity and neural communication. Different stressors impair myelinating oligodendrocytes, leading to demyelination, inflammation, and neurodegeneration. The intracellular processes underlying oligodendrocyte degeneration and death are unclear. Here, using optically targeted DNA damage that causes single-cell demyelination, we reveal that injured mature oligodendrocytes lose mitochondria within days and persist without them for weeks to months before cell death. This differs from other oligodendrocyte lineage cells, which exhibit acute mitochondrial changes followed by rapid cell death. Conditional deletion of the mitochondrial-related gene, Fis1, in mature oligodendrocytes, similarly causes acute loss of mitochondria and prolonged cell death. The unique cell death is characterized by nuclear changes, intracellular stress, and markers of disease-associated oligodendrocytes. Thus, mitochondrial loss may be an early marker of oligodendrocyte pathology, and mitochondrial quality control is required for oligodendrocyte and myelin homeostasis.

neuroscience↗

bioRxiv2025

Constitutive DREADD signalling modulates oligodendrocyte precursor cell bioelectrical membrane properties and fate

Oligodendrocyte precursor cells (OPCs) are small cells in the central nervous system that proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for myelin plasticity and repair. G protein-coupled neuromodulator receptors can regulate OPC fate, but the role of individual G protein families is unclear. Here, we use chemogenetics to directly investigate the role of Gq and Gi proteins in OPC fate. We find that expressing the DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) hM3Dq or hM4Di in OPCs without activating them with designer agonists induces constitutive G protein signalling, which alters bioelectrical membrane properties such as voltage-gated ion channels and glutamate receptors in OPCs. Further, we find that hM3Dq or hM4Di expression alone modulates OPC fate, increasing or decreasing differentiation, respectively, suggesting that directly targeting G protein signalling can be used to bidirectionally regulate differentiation. Importantly, our data raise a note of caution regarding the use of DREADDs in both excitable and non-excitable small cells. SIGNIFICANCE STATEMENTDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used to manipulate neuronal excitability. Their use in other neural cell types is rapidly increasing; however, DREADDs have not been thoroughly characterized in non-neuronal cells. Here, we show that when expressed in small excitable cells like oligodendrocyte precursor cells, DREADDs are constitutively active, unlike in excitatory neurons. This constitutive DREADD signalling alters cell fate and bioelectrical membrane properties like voltage-gated ion channels and glutamate receptors. Our data highlight that constitutive DREADD activity represents a significant confound that needs to be considered and controlled for when expressing DREADDs in small cells, and demonstrate that G protein signalling is a potent regulator of OPC fate, with a potential for therapeutic implications.

neuroscience↗

bioRxiv2024

Transient upregulation of procaspase-3 during oligodendrocyte fate decisions

Oligodendrocytes are generated throughout life and in neurodegenerative conditions from brain resident oligodendrocyte precursor cells (OPCs). The transition from OPC to oligodendrocyte involves a complex cascade of molecular and morphological states that position the cell to make a fate decision to integrate as a myelinating oligodendrocyte or die through apoptosis. Oligodendrocyte maturation impacts the cell death mechanisms that occur in degenerative conditions, but it is unclear if and how the cell death machinery changes as OPCs transition into oligodendrocytes. Here, we discovered that differentiating oligodendrocytes transiently upregulate the zymogen procaspase-3, equipping these cells to make a survival decision during differentiation. Pharmacological inhibition of caspase-3 decreases oligodendrocyte density, indicating that procaspase-3 upregulation promotes differentiation. Moreover, using procaspase-3 as a marker, we show that oligodendrocyte differentiation continues in the aging cortex and white matter. Taken together, our data establish procaspase-3 as a differentiating oligodendrocyte marker and provide insight into the underlying mechanisms occurring during the decision to integrate or die.

neuroscience↗