Phosphorylation-dependent proteome of Marcks in ependyma during aging and behavioral homeostasis in the mouse forebrain.

Autor: Muthusamy N; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA., Williams TI; Molecular Education, Technology and Research Innovation Centre (METRIC), North Carolina State University, Raleigh, NC, USA.; Department of Chemistry, North Carolina State University, Raleigh, NC, USA., O'Toole R; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Brudvig JJ; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Adler KB; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA., Weimer JM; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Muddiman DC; Molecular Education, Technology and Research Innovation Centre (METRIC), North Carolina State University, Raleigh, NC, USA.; Department of Chemistry, North Carolina State University, Raleigh, NC, USA., Ghashghaei HT; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA. tghashg@ncsu.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2022 Aug; Vol. 44 (4), pp. 2077-2094. Date of Electronic Publication: 2022 Jan 24.
DOI: 10.1007/s11357-022-00517-3
Abstrakt: Ependymal cells (ECs) line the ventricular surfaces of the mammalian central nervous system (CNS) and their development is indispensable to structural integrity and functions of the CNS. We previously reported that EC-specific genetic deletion of the myristoylated alanine-rich protein kinase C substrate (Marcks) disrupts barrier functions and elevates oxidative stress and lipid droplet accumulation in ECs causing precocious cellular aging. However, little is known regarding the mechanisms that mediate these changes in ECs. To gain insight into Marcks-mediated mechanisms, we performed mass spectrometric analyses on Marcks-associated proteins in young and aged ECs in the mouse forebrain using an integrated approach. Network analysis on annotated proteins revealed that the identified Marcks-associated complexes are in part involved in protein transport mechanisms in young ECs. In fact, we found perturbed intracellular vesicular trafficking in cultured ECs with selective deletion of Marcks (Marcks-cKO mice), or upon pharmacological alteration to phosphorylation status of Marcks. In comparison, Marcks-associated protein complexes in aged ECs appear to be involved in regulation of lipid metabolism and responses to oxidative stress. Confirming this, we found elevated signatures of inflammation in the cerebral cortices and the hippocampi of young Marcks-cKO mice. Interestingly, behavioral testing using a water maze task indicated that spatial learning and memory is diminished in young Marcks-cKO mice similar to aged wildtype mice. Taken together, our study provides first line of evidence for potential mechanisms that may mediate differential Marcks functions in young and old ECs, and their effect on forebrain homeostasis during aging.
(© 2022. The Author(s), under exclusive licence to American Aging Association.)
Databáze: MEDLINE
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