An in vitro model yields 'importin' new insights into chronic traumatic encephalopathy: damaged astrocytes stop 'thrombospondin' to the injury: An Editorial Highlight for 'Defective synthesis and release of astrocytic thrombospondin-1 mediates the neuronal TDP-43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies'

Abstract

Read the highlighted article 'Defective synthesis and release of astrocytic thrombospondin-1 mediates the neuronal TDP-43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies' on page 645.

Fig 1

(a) A putative time course of traumatic events in chronic traumatic encephalopathy (CTE) based on the in vitro model of Jayakumar et al. (2016). Following trauma, an initial increase in astrocyte thrombospondin-1 (TSP-1) synthesis and release protects neurons from toxic proteinopathy. As damaged astrocytes decrease TSP-1 secretion to neurons over time, hyperphosphorylated transactivating DNA-binding protein-43 (p-TDP-43) begins to accumulate in the neuronal cytoplasm (green line) and synaptic integrity (blue shading) begins to decline. Accumulation of hyperphosphorylated tau (p-tau, red line) is observed later in the sequence of traumatic events, subsequent to the start of cytoplasmic p-TDP-43 accumulation. (b) Schematic depiction of the trauma-induced TDP-43 pathogenic cascade regulated by astrocyte-secreted TSP-1. Early after trauma, astrocytes increase their synthesis and secretion of TSP-1, a guardian of synaptic integrity that antagonizes the trauma-induced upregulation of neuronal casein kinase-1epsilon (CK1ε), preventing TDP-43 phosphorylation (left panel). Over time, damaged astrocytes lose the ability to synthesize and secrete TSP-1, resulting in increased CK1ε expression and activity (middle panel). A decrease in the expression of importin-β, a carrier protein that translocates phosphorylated TDP-43 (p-TDP-43) to the nucleus, is also observed when astrocyte TSP-1 is absent. Consequently, p-TDP-43 accumulates in the cytoplasm due to elevated CK1ε and low importin β levels. Cytoplasmic p-TDP-43 buildup leads to its ubiquitination, a hallmark of CTE TDP-43 proteinopathy, and precedes a reduction in synaptic proteins PSD95 and the NR1 subunit of the NMDA receptor (NMDA-nr1, right panel) that indicates a loss of synaptic integrity. TDP-43 pathogenesis appears to start prior to and independent of p-tau accumulation, another CTE hallmark observed in this in vitro trauma model.