Chaperone-Mediated Autophagy after Traumatic Brain Injury

Abstract

Chaperone-mediated autophagy (CMA) and the ubiquitin-proteasomal system (UPS) are two major protein degradation systems responsible for maintaining cellular homeostasis, but how these two systems are regulated after traumatic brain injury (TBI) remains unknown. TBI produces primary mechanical damage that must be repaired to maintain neuronal homeostasis. The level of lysosomal-associated membrane protein type 2A (LAMP2A) is the hallmark of CMA activity. The level of polyubiquitinated proteins (ubi-proteins) reflects UPS activity. This study utilized a moderate fluid percussion injury model in rats to investigate the changes in CMA and the UPS after TBI. Induction of CMA was manifested by significant upregulation of LAMP2A and secondary lysosomes during the periods of 1-15 days of recovery after TBI. In comparison, the levels of ubiproteins were increased only moderately after TBI. The increases in the levels of LAMP2A and 70 kDa heat-shock protein for CMA after TBI were seen mainly in the secondary lysosome-containing fractions. Confocal and electron microscopy further showed that increased LAMP2A or lysosomes were found mainly in neurons and proliferated microglia. Because CMA and the UPS are two major routes for elimination of different types of cellular aberrant proteins, the consecutive activation of these two pathways may serve as a protective mechanism for maintaining cellular homeostasis after TBI.

Transplantation of mesenchymal stem cells overexpressing interleukin‐10 induces autophagy response and promotes neuroprotection in a rat model of TBI

“…23,42,43 Among them, IL-10 is the most important because it exerts neuroprotective effects via suppressing the expression of various pro-inflammatory cytokines, such as IFN-γ, IL-1β, IL-2, IL-6 and TNF-α, as observed in stroke 23,44 and in TBI. 42,43,[45][46][47] MSCs may secrete IL-10 under specific conditions, such as inflammatory environments observed after brain injuries. 52 Also, they may stimulate the cells surrounding the injury and trigger the secretion of IL-10 and other neurotrophic factors.…”

Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats

“…Accumulating evidence indicates that autophagy is activated in various animal models of the central nervous system, such as traumatic brain and spinal cord injury (Park et al, 2015;Li et al, 2015a), cerebral and spinal cord ischemia (Villamil-Ortiz and CardonaGomez, 2015;Li et al, 2015b), intracerebral hemorrhage (Yang et al, 2015), and neurodegeneration (Navone et al, 2015). In the model of cerebral ischemia, activated autophagy occured in different cell types such as neurons , astrocytes (Qin et al, 2010) and vascular endothelial cells (Li et al, 2013).…”

“…Autophagy is an intracellular catabolic mechanism that maintains a balance between protein synthesis and degradation, which can both promote cell survival and induce cell death (autophagic cell death) depending on the specific pathological event. Accumulating evidence has demonstrated that autophagy activation is elevated in the central nervous system under stressed conditions (Park et al, 2015;Li et al, 2015a;Villamil-Ortiz and Cardona-Gomez, 2015;Yang et al, 2015). As shown in the previous studies, autophagy plays an important role in spinal cord injury (Baba et al, 2009;Seo et al, 2015;Fujita et al, 2015); however, its expression change and mechanism after spinal cord I/R injury are largely unknown.…”

AMP‐activated protein kinase‐dependent induction of autophagy by erythropoietin protects against spinal cord injury in rats

“…Recently, autophagy has been demonstrated to be an important therapeutic mechanism for injuries of CNS such as SCI and several CNS degeneration diseases such as Alzheimer's disease. Accumulating evidence has shown that autophagy is induced after SCI, and the impairment of autophagy has been addressed to aggravate the secondary injury. The AMP‐activated protein kinase (AMPK) acts as an energy sensor responding to stress conditions such as oxidative stress and deprivation of nutrition, which also acts as a key player in autophagy.…”