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

Institute of Experimental and Clinical Pharmacology and Toxicology

9 Citations (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.

Original language	English
Article number	1318
Journal	Nature Aging
Volume	5
Issue number	3
Pages (from-to)	450-467
Number of pages	18
Publication status	Published - 03.2025

Funding

Funders	Funder number
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

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.23-06 Molecular and Cellular Neurology and Neuropathology
2.22-09 Pharmacology
2.23-05 Experimental Models for the Understanding of Nervous System Diseases

Cite this

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. Article 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, vol. 5, no. 3, 1318, pp. 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.

UR - https://www.scopus.com/pages/publications/85218232029

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M3 - Journal articles

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SP - 450

EP - 467

JO - Nature Aging

JF - Nature Aging

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M1 - 1318

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

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