Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury

Sadasivan, Shankar; Dunn, William A.; Hayes, Ronald L.; Wang, Kevin

doi:10.1016/j.bbrc.2008.05.031

Cited by 48 publications

(36 citation statements)

References 23 publications

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“…This may not be the case, because several previous studies show that mechanical stress generally activates, rather than inhibits lysosomal turnover. [43][44][45][46][47] As shown in the present study, LAMP2A is increased in both neurons and proliferated microglia (Fig. 3B).…”

Section: Fig 2 Electron Micrographs Of Neocortical Neurons After Trsupporting

confidence: 84%

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Park

Liu

Luo

et al. 2015

Journal of Neurotrauma

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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.

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Section: Fig 2 Electron Micrographs Of Neocortical Neurons After Trsupporting

confidence: 84%

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Park

Liu

Luo

et al. 2015

Journal of Neurotrauma

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“…[18][19][20] The role of autophagy in this secondary neurodegeneration is uncertain. Increased markers of autophagy have been reported in the brain following TBI; [21][22][23][24] however, its cell-type specificity and the mechanism of induction remain unclear. Moreover, the function of autophagy following TBI is controversial, with both beneficial and detrimental roles suggested.…”

Section: Introductionmentioning

confidence: 99%

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

et al. 2014

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Keywords: autophagy, autophagy flux, lysosome, neuronal cell death, traumatic brain injury Abbreviations: ACTB, actin; b; AIF1/IBA1, allograft inflammatory factor 1; AIFM1, apoptosis-inducing factor, mitochondrion-associated, 1; APC, adenomatous polyposis coli; ATG12, autophagy-related 12; ATG5, autophagy-related 5; ATG7, autophagy-related 7; CAPS12, caspase 12; CASP3, caspase 3; CCI, controlled cortical impact; CD68, CD68 molecule; CSPG4, chondroitin sulfate proteoglycan 4; CTSD, cathepsin D; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC3, microtubule associated protein 1 light chain 3; RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; SPTAN1, spectrin, a, non-erythrocytic 1; SQSTM1, sequestosome 1; TBI, traumatic brain injury; ULK1, unc-51 like autophagy activating kinase 1.Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1-3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death.

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“…[9][10][11][12][13][14]26,27 The first study investigating the association between autophagy and TBI was conducted by Diskin and colleagues. 11 In that study, it was demonstrated that Beclin-1 level dramatically increased near the site of injury in the closed-head injury model in mice.…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38][39][40][41][42][43] Besides, brain trauma conditions have been found to regulate interaction between endogenous Bcl-2 and Beclin-1 by altering their total protein levels. 27 Collectively, autophagy negatively modulates neuronal cell death in a complex manner, in order to attenuate hippocampal cell death after post-TBI hypothermia.…”

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confidence: 99%

Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury

Jin

Lin

Feng

et al. 2015

Journal of Neurotrauma

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Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37°C); sham injury with hypothermia group (32°C); TBI with normothermia group (TNG; 37°C); and TBI with hypothermia group (THG; 32°C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32°C) was achieved by partial immersion in a water bath (0°C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferasemediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy. At 24 h after TBI, the cell death index was 27.90 -2.36% in TNG and 14.90 -1.52% in THG. Expression level of LC3 and Beclin-1 were significantly increased after TBI and were further up-regulated after post-TBI hypothermia. Further, ultrastructural observations showed that there was a marked increase of autophagosomes and autolysosomes in ipsilateral hippocampus after post-TBI hypothermia. Our data demonstrated that moderate hypothermia significantly attenuated cell death and increased autophagy in ipsilateral hippocampus after fluid percussion TBI. In conclusion, autophagy pathway may participate in the neuroprotective effect of post-TBI hypothermia.

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Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury

Cited by 48 publications

References 23 publications

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury

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