Fight Aging!

The axons connecting neurons of the nervous system are sheathed in a layer of myelin. This myelination of axons is necessary for the transmission of electrochemical signals through the nervous system. When the myelin layer becomes extensively damaged, whatever the cause, the result is profoundly disabling conditions such as multiple sclerosis. Over the course of late life aging, the myelin sheathing of axons is disrupted to a lesser but still meaningful degree. It is thought that age-related degradation of myelin in the brain contributes to cognitive impairment, for example. This is why it is worth keeping an eye on progress towards novel therapies that might induce repair of myelin.

The myelin sheathing of axons is maintained by a population of cells known as oligodendrocytes. In today's open access paper, researchers outline their discovery of a regulator of this population size. Expression of C1ql1 regulates the pace at which oligodendrocytes are produced from a population of progenitor cells; the more oligodendrocytes, the greater the repair of damaged myelin. This offers a potential point of intervention, a basis for therapies that work by increasing C1ql1 expression. Such therapies may be useful not just for the treatment of demyelinating conditions, but also offer a way to reverse the age-related damage to myelin.

C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation

The myelination of axons by oligodendrocytes in the central nervous system (CNS) is essential for proper nervous system function. Mature oligodendrocytes are post-mitotic and arise through a stepwise differentiation process from resident oligodendrocyte progenitor cells (OPCs). Oligodendrocytes that arise during development may have very long lifespans, perhaps equal to the longevity of the animal itself; it is, therefore, curious that a remarkable ~5% of all cells in the adult CNS remain as OPCs. This resident pool of OPCs represents a potential source of new oligodendrocytes important for cognition and learning and also to replace those lost to injury or inflammation in diseases such as multiple sclerosis (MS).

Proteins of the C1q/tumor necrosis factor (TNF) superfamily have recently gained attention for their role at neuronal synapses. Among these, the complement C1q-like (C1QL) proteins, encoded by four paralogous genes (C1ql1, C1ql2, C1ql13, C1ql14), have drawn significant interest. In the CNS, C1QL proteins are typically expressed in a small subset of neurons, are secreted from pre-synaptic terminals, reside in the synaptic cleft, and function to promote synapse formation and/or maintenance. We have determined that C1QLs bind to a post-synaptically localized G protein-coupled receptor (GPCR) called adhesion GPCR B3 (ADGRB3).

C1QL1 and ADGRB3 likely have pleiotropic functions beyond neuron-neuron synapses. We have recently shown that most C1QL1-expressing cells in the brain co-express the transcription factor OLIG2, indicating that they are of the oligodendrocyte lineage. This suggests that C1QL1-ADGRB3 signaling from glia is associated with remyelination potential. Therefore, we investigated whether C1QL1 has a function in regulating OPC differentiation. We show that C1ql1 is expressed by OPCs, and in most brain regions, is the only cell type expressing C1ql1. To uncover the function of C1QL1, we created OPC-specific conditional knockout (cKO) mice and found that C1ql1 removal from OPCs causes a developmental delay in oligodendrocyte cell density and myelination, but mice recover by adulthood. After mice were challenged by cuprizone-induced demyelination, we found cKO mice had a reduced or delayed oligodendrocyte density and remyelination recovery, while a virus that we designed to overexpress C1QL1 caused an increase in oligodendrocyte density and myelination during recovery.

To study possible mechanistic explanations for these phenotypes, we used primary OPC cultures in vitro and found that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation into oligodendrocytes. Our combined results suggest that C1QL1 signaling may have therapeutic potential for treating demyelinating diseases such as MS.