A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience

Manon Rivagorda; David Romeo-Guitart; Victoria Blanchet; François Mailliet; Valérie Boitez; Natalie Barry; Dimitrije Milunov; Eleni Siopi; Nicolas Goudin; Stéphanie Moriceau; Chiara Guerrera; Michel Leibovici; Soham Saha; Patrice Codogno; Eugenia Morselli; Etienne Morel; Anne-Sophie Armand; Franck Oury

A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience

Manon Rivagorda, David Romeo-Guitart, Victoria Blanchet, François Mailliet, Valérie Boitez, Natalie Barry, Dimitrije Milunov, Eleni Siopi, Nicolas Goudin, Stéphanie Moriceau, Chiara Guerrera, Michel Leibovici, Soham Saha, Patrice Codogno, Eugenia Morselli, Etienne Morel, Anne-Sophie Armand, Franck Oury

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

19 Zitate (Scopus)

Abstract

Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.

Originalsprache	Englisch
Aufsatznummer	1318
Zeitschrift	Nature Aging
Jahrgang	5
Ausgabenummer	3
Seiten (von - bis)	450-467
Seitenumfang	18
Publikationsstatus	Veröffentlicht - 03.2025

Fördermittel

We thank N. Dupont for critical suggestions during the course of the study. We thank the Viral Production, Imaging, Proteomics, Histology, Behavioral and Metabolism and Animal House Facility platforms of SFR Necker. This work was supported by FRM Labellisation (F.O. and M.R.), HFSP (F.O.), ANR (ciliophaging) (F.O. and E. Morel), the NRJ Foundation for Neuroscience (F.O.), the ATIP-AVENIR Program (F.O.), Emergence Ville de Paris (F.O.), AGEMED-INSERM (F.O.), INSERM-Transfer (F.O.), FSER (F.O.), MSCA (D.R.-G.) and the InterAging program (F.O. and V. Blanchet).

Träger	Trägernummer
AGEMED-INSERM
INSERM-Transfer
Agence Nationale de la Recherche
H2020 Marie Skłodowska-Curie Actions
ATIP-AVENIR
NRJ Foundation for Neuroscience
Emergence Ville de Paris
Fondation Schlumberger pour l’Education et la Recherche
FRM Labellisation
Human Frontier Science Program

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie
2.22-09 Pharmakologie
2.23-05 Experimentelle Modelle zum Verständnis von Erkrankungen des Nervensystems

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Rivagorda, M., Romeo-Guitart, D., Blanchet, V., Mailliet, F., Boitez, V., Barry, N., Milunov, D., Siopi, E., Goudin, N., Moriceau, S., Guerrera, C., Leibovici, M., Saha, S., Codogno, P., Morselli, E., Morel, E., Armand, A.-S., & Oury, F. (2025). A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience. Nature Aging, 5(3), 450-467. Artikel 1318.

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title = "A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience",

abstract = "Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.",

author = "Manon Rivagorda and David Romeo-Guitart and Victoria Blanchet and Fran{\c c}ois Mailliet and Val{\'e}rie Boitez and Natalie Barry and Dimitrije Milunov and Eleni Siopi and Nicolas Goudin and St{\'e}phanie Moriceau and Chiara Guerrera and Michel Leibovici and Soham Saha and Patrice Codogno and Eugenia Morselli and Etienne Morel and Anne-Sophie Armand and Franck Oury",

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Rivagorda, M, Romeo-Guitart, D, Blanchet, V, Mailliet, F, Boitez, V, Barry, N, Milunov, D, Siopi, E, Goudin, N, Moriceau, S, Guerrera, C, Leibovici, M, Saha, S, Codogno, P, Morselli, E, Morel, E, Armand, A-S & Oury, F 2025, 'A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience', Nature Aging, Jg. 5, Nr. 3, 1318, S. 450-467.

TY - JOUR

T1 - A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience

AU - Rivagorda, Manon

AU - Romeo-Guitart, David

AU - Blanchet, Victoria

AU - Mailliet, François

AU - Boitez, Valérie

AU - Barry, Natalie

AU - Milunov, Dimitrije

AU - Siopi, Eleni

AU - Goudin, Nicolas

AU - Moriceau, Stéphanie

AU - Guerrera, Chiara

AU - Leibovici, Michel

AU - Saha, Soham

AU - Codogno, Patrice

AU - Morselli, Eugenia

AU - Morel, Etienne

AU - Armand, Anne-Sophie

AU - Oury, Franck

PY - 2025/3

Y1 - 2025/3

N2 - Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.

AB - Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.

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M3 - Journal articles

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EP - 467

JO - Nature Aging

JF - Nature Aging

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ER -

A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

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