Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Proinflammatory Microenvironment and Early Spatial Memory Impairment

Tonie Farris
,
Salvador Gonzalez Ochoa
ORCID logo ,
Muna Mohammed
,
Harshana Rajakaruna
,
Jane Tonello
,
Thanigaivelan Kanagasabai
ORCID logo ,
Olga Korolkova
,
Akiko Shimamoto
,
Alla V Ivanova
* ORCID logo ,
Anil Shanker
* ORCID logo
Version 1 : Received: 3 May 2024 / Approved: 7 May 2024 / Online: 7 May 2024 (08:17:45 CEST)

How to cite: Farris, T.; Gonzalez Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A. V.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Proinflammatory Microenvironment and Early Spatial Memory Impairment. Preprints 2024, 2024050349. https://doi.org/10.20944/preprints202405.0349.v1 Farris, T.; Gonzalez Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A. V.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Proinflammatory Microenvironment and Early Spatial Memory Impairment. Preprints 2024, 2024050349. https://doi.org/10.20944/preprints202405.0349.v1

Abstract

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

Keywords

aging; neuroinflammation; cognitive impairment; Tusc2; Fus1; mitochondria; calcium; brain immune populations; sex-dependent changes

Subject

Biology and Life Sciences, Aging

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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