Summary
Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease but their role is poorly understood. Here we show that A1 reactive astrocytes are induced by classically-activated neuroinflammatory microglia. We show that activated microglia induce A1s by secreting Il-1α, TNFα, and C1q, and that these cytokines together are necessary and sufficient to induce A1s. A1s lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when A1 formation is blocked. Finally, we show that A1s are highly present in human neurodegenerative diseases including Alzheimer’s, Huntington’s, Parkinson’s, ALS, and Multiple Sclerosis. Taken together these findings explain why CNS neurons die after axotomy, strongly suggest that A1s help to drive death of neurons and oligodendrocytes in neurodegenerative disorders, and point the way forward for developing new treatments of these diseases.
Highlights d CD49f is a novel, reactivity-independent marker for human astrocytes d CD49f can be used to purify human fetal astrocytes and iPSCderived astrocytes d CD49f + hiPSC-astrocytes acquire an A1-like reactive state upon cytokine stimulation d CD49f + A1-like reactive astrocytes are dysfunctional and toxic to neurons in vitro
Reactive astrocytes have been implicated in the pathogenesis of neurodegenerative diseases, including a non-cell autonomous effect on motor neuron survival in ALS. We previously defined a mechanism by which microglia release three factors, IL-1α, TNFα, and C1q, to induce neurotoxic astrocytes. Here we report that knocking out these three factors markedly extends survival in the
SOD1
G93A
ALS mouse model, providing evidence for gliosis as a potential ALS therapeutic target.
The spinal cord is a fascinating structure responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. We profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (γ*). Collectively, these data provide a single-cell transcriptional atlas (
http://spinalcordatlas.org
) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.
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