Abstract
Recently, we have reported that heat shock protein B1 (HSPB1) and purinergic receptor P2X7 (P2RX7) are involved in astroglial autophagy (clasmatodendrosis), following status epilepticus (SE). However, the underlying mechanisms of astroglial autophagy have not been completely established. In the present study, we found that the lacking of P2rx7 led to prolonged astroglial HSPB1 induction due to impaired mitogen-activated protein kinase 1/2 (MAPK1/2)-mediated specificity protein 1 (SP1) phosphorylation, following kainic acid-induced SE. Subsequently, the upregulated HSPB1 itself evoked ER stress and exerted protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1, AMPK1)/unc-51 such as autophagy activating kinase 1 (ULK1)- and AKT serine/threonine kinase 1 (AKT1)/glycogen synthase kinase 3 beta (GSK3B)/SH3-domain GRB2-like B1 (SH3GLB1)-mediated autophagic pathways, independent of mechanistic target of rapamycin (MTOR) activity in astrocytes. These findings provide a novel purinergic suppression mechanism to link chaperone expression to autophagy in astrocytes. Therefore, we suggest that P2RX7 may play an important role in the regulation of autophagy by the fine-tuning of HSPB1 expression.
Highlights
Astrocytes regulate extracellular ion homeostasis, brain–blood barrier, and energy metabolism that are essential for neuronal survival and synaptic function[1]
BzATP induced astroglial apoptosis 7 days after kainic acid (KA) injection (p < 0.05 vs. vehicle; Supplementary Figure 5C-D), while the vehicle and A740003 did not (Supplementary Figure 5CD). These findings suggest that P2RX7 inhibition may accelerate heat shock protein B1 (HSPB1) induction and autophagy, while P2RX7 activation may induce apoptosis in astrocytes accompanied by reduction in HSPB1 expression
P2rx[7] deletion led to prolonged HSPB1 induction, which facilitated astroglial autophagy via two different signaling pathways following KA injection (Fig. 8)
Summary
Astrocytes regulate extracellular ion homeostasis, brain–blood barrier, and energy metabolism that are essential for neuronal survival and synaptic function[1]. Because of reactive astrogliosis[2], astrocytes are believed to be resistant to harmful stresses. A growing body of evidence demonstrates that astroglial damage occurs before or after reactive astrogliosis in epilepsy[3,4], brain ischemia[5,6], and Alzheimer’s disease[7]. More than 100 years ago, Alzheimer reported irreversible astroglial injury characterized by extensive swollen vacuolized cell bodies and disintegrated/beaded processes, and Cajal termed it as “clasmatodendrosis”[8]. We have reported that status epilepticus (SE, a continuous unremitting seizure activity) evokes clasmatodendrosis, which is involved in the Unexpectedly, we have found that vacuoles in clasmatodendritic astrocytes are lysosome-associated membrane protein 1 (LAMP1)-positive, which is required for the essential activation of autophagy[9,15]. We have reported that clasmatodendrosis may be P2RX7-mediated astroglial autophagy[10]
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