Project description:Astrocyte responses to neuronal injury may be beneficial or detrimental to neuronal recovery, but the mechanism that determines these different responses are poorly understood. Transcriptional analysis showed that EphB1 induces a protective inflammatory signature in astrocytes, which is distinct from the response evoked by interleukin (IL)-6, which is known to have both pro- and anti-inflammatory properties. We demonstrate that this beneficial EphB1 induced signaling pathway is disrupted in astrocytes derived from human induced pluripotent stem cells (iPSC) of amyotrophic lateral sclerosis (ALS) patients.
Project description:Astrocyte responses to neuronal injury may be beneficial or detrimental to neuronal recovery, but the mechanism that determines these different responses are poorly understood. Transcriptional analysis showed that EphB1 induces a protective inflammatory signature in astrocytes, which is distinct from the response evoked by interleukin (IL)-6, which is known to have both pro- and anti-inflammatory properties. We demonstrate that this beneficial EphB1 induced signaling pathway is disrupted in astrocytes derived from human induced pluripotent stem cells (iPSC) of amyotrophic lateral sclerosis (ALS) patients.
Project description:Reactive astrocytes are implicated in Amyotrophic Lateral Sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined astrocyte translatome sequencing (TRAP-seq) from a SOD1 mouse model, which revealed a significant number of transcripts with reduced IR in ALS are upregulated in translation. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. These results provide novel insights into the molecular factors controlling the reactive transformation of ALS astrocytes.