Upregulated functionality of mitochondria-associated ER membranes in a mouse model of traumatic brain injury

Agrawal, R. R.; Larrea, D.; Shi, L.; Song, D.; Xu, Y.; Yun, T. D.; Emmanuele, V.; Cummins, L. G.; Macaluso, F. P.; Kernie, S. G.; Min, W.; Deckelbaum, R. J.; Area-Gomez, E.

doi:10.1101/2020.11.13.381756

bioRxiv · 10.1101/2020.11.13.381756

Upregulated functionality of mitochondria-associated ER membranes in a mouse model of traumatic brain injury

Agrawal, R. R.·Larrea, D.·Shi, L.·Song, D.·Xu, Y.·Yun, T. D.·Emmanuele, V.·Cummins, L. G.·Macaluso, F. P.·Kernie, S. G.·Min, W.·Deckelbaum, R. J.·Area-Gomez, E.

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Abstract

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimers disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-{beta} as well as its precursor, APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated ER membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/381756v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@12d0989org.highwire.dtl.DTLVardef@1cd1eb2org.highwire.dtl.DTLVardef@19a56caorg.highwire.dtl.DTLVardef@1b7f3e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Agrawal, R. R., Larrea, D., Shi, L., Song, D., Xu, Y., Yun, T. D., Emmanuele, V., Cummins, L. G., Macaluso, F. P., Kernie, S. G., Min, W., Deckelbaum, R. J., Area-Gomez, E.. 2020-11-15. Upregulated functionality of mitochondria-associated ER membranes in a mouse model of traumatic brain injury. https://doi.org/10.1101/2020.11.13.381756

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