ESR6: “Role of telomeres in neuronal ageing”

IRCAN (E. Gilson group): Role of telomeres in neuronal ageing

i. Objective of research: To identify the role of telomeres in long-lived post-mitotic cells during ageing.

ii. Current state of the art: With respect to cellular ageing, long-lived post-mitotic cells (LLPMCs), such as myofibers and neurons, may live for decades in the organism. It is generally accepted that mitochondrial dysfunction and impaired autophagy are responsible for the progressive functional decline of LLPMCs. However, the causal mechanisms driving these age-related cellular changes remain elusive. The programmed somatic erosion of telomeric DNA acts as a mitotic clock of senescence. However, evidence for changes in telomeres during LLPMC ageing remains limited. Interestingly, the decreased expression of TRF2, a key subunit of the shelterin capping protein complex, occurs during neuronal and muscular tissues ageing. We recently showed that TRF2 has extratelomeric roles in regulating the expression of a neuronal gene network  and have unpublished results revealing that TRF2 downregulation in myotubes leads to mitochondrial dysfunction and ROS production. Interestingly, in this setting, FOXO3A is recruited to telomeres where it acts as a protective factor. Based on these findings, we propose that: i. telomeres are reorganized during LLPMC ageing; ii. Shelterin controls the longevity of LLPMCs; iii. a programmed shelterin alteration contributes to the progressive functional decline of LLPMCs during ageing; and iv. FOXO3A controls telomere protection during LLPMC ageing.

iii. Research methodology and approach: We will study the role of telomeres in neuronal ageing giving emphasis on the TRF2-mitochondria-FOXO3A axis that we recently revealed in myotubes (manuscript in revision). First, our ESR will compare “young” and “old” neurons isolated from wild-type and accelerated ageing mouse models to test for telomere alterations e.g. DNA length, t-loop formation, DNA damage, expression of telomeric factors. Then, our ESR will investigate the cause and consequence of TRF2 downregulation and telomeric alterations in aged neurons. In particular, our ESR will analyze the impact of telomere dysfunction and the “aged” cellular environment (conditioned medium of senescent cells) in cultured neurons on genome stability, mitochondrial and autophagy activities, the FOXO3A pathway and the axonal transport. In parallel, our ESR will study the consequences conditional TRF2 ablation in neuronal function in vivo using the Nestin-CreERT2 (already generated) and CamK-CreERT2 (to be generated) drivers.

iv. Originality and innovative aspects of the ESR project: Using cellular and mouse models, the ESR will explore unexpected links between non-dividing cell ageing and telomeres. This should allow the development of new interventional strategies to prevent and cure age-related neuronal disorders.

v. Integration of the ESR project to the overall research programme: Our ESR will work with the Garinis and the Lopez-Otin on neuronal samples derived from premature ageing animal models for telomeric phenotyping and with the Auwerx and the Tavernarakis groups for an in-depth analysis of the mitochondrial changes triggered by telomere dysfunction.