Open Access
Smelling the dark proteome: functional characterization of PITH domain-containing protein 1 (C1orf128) in olfactory metabolism
(American Chemical Society, 2020) Lachén Montes, Mercedes; Mendizuri, Naroa; Ausín, Karina; Pérez Mediavilla, Alberto; Azkargorta, Mikel; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Iloro, Ibon; Elortza, Félix; Kondo, Hiroyuki; Ohigashi, Izumi; Ferrer, Isidro; Torre, Rafael de la; Robledo, Patricia; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1-/- mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.
Open Access
Impact of medication use on olfactory performance in older adults
(Frontiers Media, 2025-04-03) Izco-Cubero, Maite; Zambom Ferraresi, Fabíola; Zambom Ferraresi, Fabrício; Fernández González de la Riva, María Luisa; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Lachén Montes, Mercedes; Lasarte, Juan José; Uzcanga Lacabe, María Iciar; Fernández, Secundino; Sanjurjo San Martín, Gloria; Maravi Aznar, Enrique; Martínez Velilla, Nicolás; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Introduction: Olfactory dysfunction impacts quality of life, safety, and nutrition. Despite its relevance among older adults, the role of medications in influencing olfactory performance remains understudied. This research investigates whether olfactory alterations in older adults are associated with the type or number of medications prescribed. Methods: An observational cross-sectional study was conducted with 107 participants (mean age of 86.1 ± 5.1 years). Olfactory performance was evaluated using the Sniffin’ Sticks Test (SST). Functional capacity, cognitive function and the number and type of medications were also assessed. Results: The analysis demonstrated a correlation between better olfactory performance and higher cognitive function. An inverse correlation was found between the age of participants and olfactory identification. While polypharmacy (intake of five or more medications) did not show a significant association with olfactory dysfunction, the intake of laxatives was associated with poorer olfactory threshold performance (−1.21, 95% CI −2.07 to −0.34; p = 0.008). In contrast, proton pump inhibitors (PPIs) (1.14, 95% CI 0.07 to 2.21; p = 0.04) and vitamin D (1.09, 95% CI 0.03 to 2.15; p = 0.04) intake were linked to improved olfactory identification. Discussion: These findings suggest that certainmedications influence olfactory performance; however, further research is needed to clarify the effects of different drug classes on olfaction.
Open Access
Involvement of glucosamine 6 phosphate isomerase 2 (GNPDA2) overproduction in beta-amyloid- and Tau P301L-driven pathomechanisms
(MDPI, 2024) Lachén Montes, Mercedes; Cartas Cejudo, Paz; Cortés, Adriana; Anaya-Cubero, Elena; Peral, Erika; Ausín, Karina; Díaz-Peña, Ramón; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Ciencias de la Salud; Osasun Zientziak
Alzheimer’s disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route.
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 Zientziak
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.

Santamaría Martínez, Enrique

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