Cartas Cejudo, Paz
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Cartas Cejudo
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Paz
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Ciencias de la Salud
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Publication Open Access Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer's and Parkinson's diseases(BMC, 2023) Cartas Cejudo, Paz; Lachén Montes, Mercedes; Ferrer, Isidro; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Ciencias de la Salud; Osasun ZientziakBackground Smell impairment is one of the earliest features in Alzheimer’s (AD) and Parkinson’s diseases (PD). Due to sex diferences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated with olfactory dysfunction. Methods SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workfows were applied in 57 post-mortem olfactory tracts (OT) derived from controls with no known neurological history (n=6F/11M), AD (n=4F/13M) and PD (n=7F/16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas. Results 327 and 151 OT diferentially expressed proteins (DEPs) were observed in AD women and AD men, respec‑ tively (35 DEPs in common). With respect to PD, 198 DEPs were identifed in PD women, whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interac‑ tion networks and widespread sex-dependent pathway perturbations in a disease-specifc manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profle across the olfactory–entorhinal–amygdaloid axis, evidencing disease-, sex- and brain structure-dependent changes in olfactory protein acetylation. Conclusions Alteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profle observed across the olfactory pathway-associated brain regions in AD and PD indicates difer‑ ential NAD (+)-dependent deacetylase mechanisms between women and men. All these data shed new light on diferential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies.Publication Open Access Deregulated transcription and proteostasis in adult mapt knockout mouse(MDPI, 2023) Andrés Benito, Pol; Flores, África; Busquet-Areny, Sara; Carmona, Margarita; Ausín, Karina; Cartas Cejudo, Paz; Lachén Montes, Mercedes; Río, José Antonio del; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Ferrer, Isidro; Ciencias de la Salud; Osasun ZientziakTranscriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, ¿-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.