Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer's and Parkinson's diseases
Fecha
2023Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Identificador del proyecto
Impacto
|
10.1186/s13293-023-00487-x
Resumen
Background 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 therapeuti ...
[++]
Background 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. [--]
Materias
Alzheimer,
Olfaction,
Parkinson,
Proteomics,
Sexual dimorphism,
Sirtuin
Editor
BMC
Publicado en
Biology of Sex Differences, (2023) 14:5
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
The Proteomics Platform of Navarrabiomed was member of Proteored (PRB3-ISCIII) supported by grant PT17/0019/009, of the PE I+D+I 2013–2016 funded by ISCIII and FEDER. The Clinical Neuroproteomics Unit of Navarrabiomed is member of the Global Consortium for Chemosensory Research (GCCR) and the Spanish Olfactory Network (ROE) (supported by grant RED2018-102662-T funded by Spanish Ministry of Science and Innovation). This work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033). to J.F.-I. and E.S.) and the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2020-000028 to E.S.). PC-C was supported by a predoctoral fellowship from the Public University of Navarra (UPNA).