OsteoCalcin Autophagy to reJuvenate motoneuronAL function

Project Information

CAJAL

Grant agreement ID: 101029060

DOI

10.3030/101029060

Project closed

EC signature date 17 March 2021

Start date 1 June 2021

End date 31 May 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 184 707,84

EU contribution

€ 184 707,84

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - CAJAL (OsteoCalcin Autophagy to reJuvenate motoneuronAL function)

Reporting period: 2021-06-01 to 2023-05-31

Summary of the context and overall objectives of the project

The action “Osteocalcin Autophagy to rejuvenate motoneuronal function” analyzed the role of systemic factors, focusing on how the bone-borne hormone osteocalcin is crucial for maintaining locomotion during ageing. This topic has crucial societal relevance as life expectancy is expected to increase, and ageing is associated with a decline in tissue performance, leading to impaired physiological functions. However, the process that leads to motoneuron dysfunction and locomotor performance decline remains largely unknown, and there are no available/on-going therapies to slow it down. Therefore, discovering novel anti-ageing pathways in neurons may pave the way for novel therapeutic strategies to prevent/treat the age-related decline of our locomotor functions.

Prior to CAJAL, several studies have highlighted the importance of circulating factors in maintaining of optimal nervous system functions such as cognitive fitness, but none of them have unraveled the role of these factors in locomotion. The overall aim of CAJAL has been to be the first study to elucidate the impact of the systemic factors/Osteocalcin on spinal cord motoneurons, and to evaluate its therapeutic potential to prevent and/or treat age-related decline of motor function. Specific objectives have been: 1) Characterize the impact of systemic milieu/Ocn in regulating autophagy in spinal motoneurons; 2) Analyze the therapeutic potential of Ocn in age-related locomotor decline; 3) Decipher the role of Ocn-dependent autophagy in locomotor function and its signaling pathway. A parallel aim of the action, but of equal relevance, has been to foster the Fellow's research trajectory and pave his way for the further development of his career.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The work of CAJAL has been carried out through 6 work packages, which have included management, specific training for the fellow, exploitation and dissemination of results, and the experimental objectives to decipher the role of Ocn in motoneuronal autophagy and its therapeutic effect in ageing.

Regarding the results obtained in WP2-4, by using genetic modulation of Ocn/Gpr158 (Ocn's receptor), we have shown that systemic factors affect locomotor functions. In addition, we have shown that Ocn/Gpr158 coupling regulates autophagy in spinal cord MNs and that this is essential for locomotion. These data led to the development of a novel therapeutic approach to treat age-related locomotor decline by restoring systemic levels of Ocn.

For WP5 and 6, which included training and knowledge transfer, dissemination and exploitation, the researcher attended a training course focused on ageing (Advanced Cajal Course), attended international and national meetings, and developed expertise in writing articles, grants and patent applications. In total, the fellow has supervised BSc, MSc, and PhD students, presented his research through poster presentations (4 in total), will publish several articles as first or co-author (including national and international collaborations) and is preparing the application of 2 patents on novel ageing therapies. All at all, fellow’s expertise in young researchers training, writing grants and publications, and in intellectual property rights has been expanded beyond expected. In my personal opinion, I have developed a deeper knowledge of ageing biology, autophagy, and systemic factors, and have developed agility in cutting-edge approaches and lab management. I have also started my own network in Spanish autophagy and European neuroscience fields, which will be crucial for my career.

Results of CAJAL are/will be reported in 1) forthcoming papers about the role of Ocn and autophagy in locomotion, 2) patents, and 3) future poster/oral communications in national and international meetings.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

CAJAL has pushed the frontiers of research in ageing, locomotion, and autophagy, by combining novel concepts of neurobiology and systemic factors leading to the discovery of a novel bone-spinal cord communication. In this way, CAJAL could act as a scientific amplifier in the near future, leading to new explorations of how ageing/systemic factors affect locomotion, and how autophagy controls this fine-controlled neuronal function. The action may bring the locomotor system into focus, as most studies to date have focused on brain ageing without considering other components of the central nervous system. Furthermore, it also opens the door to investigating the ageing of the peripheral nervous system, since there is a loss of motor axons and neuromuscular junctions. In fact, the action has created a new line of research in the Host laboratory and has broadened the research topics present there.

CAJAL could also have a socio-economic impact, as understanding the cellular and molecular mechanisms that promote ageing can help the development of new approaches. For example, understanding how autophagy is essential for maintaining neuronal functions, and how systemic factors impact on this cellular mechanism, could open new lines of research in both the public and private sectors, thereby promoting economic development. Finally, the fellow hopes/wishes that his informal communication with non-scientific audiences has raised awareness of the social problem of ageing and the type of research that is being conducted to address it.

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