1. Mitochondrial quality control in ageing and neurodegeneration
   Understanding how mitochondrial quality control mechanisms regulate age-related memory decline and motoneuron degeneration.

2. Neddylation as a post-translational regulator of memory
   Investigating how neddylation controls neuronal homeostasis and cognitive function during ageing.

3. Primary cilia as regulators of neuronal function
   Investigating how primary cilia regulate memory and locomotor function through the modulation of autophagy.

During my 2nd postdoc (Paris)

1. Bone regulates locomotor function by maintaining mitochondrial function (MSCA Fellowship). This work provided the first evidence that a bone-derived hormone can control locomotor function by sustaining mitochondrial function in motoneurons, and that disruption of this bone–motoneuron axis contributes to age-related locomotor decline. Beyond this finding, the project established my expertise in assessing mitochondrial function, including neuronal mitochondrial activity, mitophagy and mitochondrial quality control, and integrating these readouts with functional outcomes in aged animals.

2. Reactivation of autophagy by SIRT1-dependent epigenetics provides cognitive resilience. In this project, we investigated how body–brain communication shapes hippocampal epigenetics during ageing. We first showed that the anti-ageing hormone osteocalcin (OCN) modulates neuronal deacetylation, with SIRT1 acting as a central mediator of its effects. By combining neuronal nuclei sorting with CUT&Tag profiling, we demonstrated that SIRT1 regulates age-related cognitive decline through the epigenetic control of autophagy. Reactivation of this SIRT1-dependent epigenetic program restores autophagy and promotes cognitive resilience during ageing.

3. Neuronal primary cilia as a hormonal gateway regulating memory through autophagy. A major unresolved question in the body–brain crosstalk field is how hippocampal neurons detect and respond to changes in the systemic milieu, including circulating hormones. The primary cilium (PC) is an understudied cellular structure that functions as a signaling hub for G protein-coupled receptors (GPCRs), including hormone receptors. We hypothesized that the bone-derived hormone osteocalcin (OCN) may regulate memory through this structure. By manipulating key primary cilium proteins and combining these approaches with behavioural testing, we showed that: i) PC-dependent autophagy preserves memory fitness; ii) PC function declines with ageing, and its restoration ameliorates age-related memory decline; and iii) the PC integrates the pro-cognitive effects of osteocalcin. This work laid the foundation for investigating the primary cilium as a key cellular interface linking systemic signals to neuronal autophagy and cognitive function.

4.  Role of phosphate transporters in cognition and memory. Slc20a1 and Slc20a2 were known as phosphate transporters, yet their role in the brain was unclear. We showed that both are essential for memory: Slc20a1 through vesicular trafficking and Slc20a2 through neuronal survival. Unexpectedly, these functions are independent of their phosphate transport activity, uncoupling a transporter from its canonical role. 

During my 1st postdoc (Barcelona)

1. 1. GRP78-dependent mitophagy prevents motoneuron degeneration. Using unbiased proteomics, we found that the neuroprotective effects of the chaperone GRP78 are mediated through mitochondrial pathways and demonstrated that GRP78 promotes protective mitophagy. This study provided the first evidence linking GRP78 to mitochondrial quality control. It was also my first study in mitochondrial biology and marked the beginning of my interest in mitochondria as key regulators of neuronal resilience. This line of research ultimately led to the questions addressed by MitoEpiAge, extending my focus from mitochondrial quality control to the regulation of the mitochondrial genome during ageing.

   2. Elucidate the hypoalgesic effects of NeuroHeal in neuropathic pain after peripheral nerve injury. We explored the effects of NeuroHeal in two in vivo models of neuropathic pain. Moreover, we observed that NeuroHeal may reduce painful sensations by the modulation of P2X4-BDNF-KCC2 pathway.

   3. Describe the effects of SIRT2 inhibition and its downstream mechanisms in motor axon regeneration after peripheral nerve injury. We used KO SIRT2 mice and in vitro models to analyze the role of SIRT2 in neuritogenesis and motor recovery after nerve injury. Here, we observed that the blockage of  SIRT2 promotes a p300-dependent axonal growth that includes GAP43 levels.

   4. SIRT1/Hif1a-dependent autophagy to recover proper function after a  peripheral nerve injury. SIRT1 is translocated to the cytosol when motoneurons need to regenerate their axon. This, promotes the stabilization of Hif1, which leads to an increase in autophagy flux that enhances motor regeneration after nerve injury.

   5. Elucidate the effects of NeuroHeal in muscle atrophy models. We deciphere the capacity of NeuroHeal to reduce muscle atrophydue to neurogenic denervation or disuse of the limbs. We observed that NeuroHeal modulates the autophagy associated with muscle atrophy.

During my PhD

1. Analyze the potential of Systems biology and artificial intelligence approaches to discover novel drug therapies for nervous trauma. With the aid of in vivo models of peripheral nerve injury, Systems biology, and artificial intelligence, we obtained novel drug therapies to neuroprotect motoneurons after nerve root avulsion. Afterthat, we discovered NeuroHeal therapy, which has wide-range protective effects (increases neuronal survival, activates Sirtuin1, promotes regeneration, and reduces gliosis).

2. Importance of SIRT2 and SIRT1 in MN death and neuronal endoplasmic reticulum stress. We used pharmacological treatments and transgenic mice (overexpressing SIRT1 or KO for SIRT2) to analyze the role of SIRT1 and SIRT2 in motoneuronal death after hypoglossal nerve axotomy and under endoplasmic reticulum stress.  Strikingly, we depictured that SIRT2 activity facilitates neuronal survival by modulating microglial reaction.

3. Role of SIRT1-dependent autophagy in neonatal motoneurons death.  We took advantage of an in vivo model of neonatal motoneuron death, to test the anti-apoptosis effects of NeuroHeal. We observed that NeuroHeal fine-tunes autophagy by SIRT1/AKT/FOXO3a axis, which reduces apoptosis and leads to increased neuronal survival after nerve injury during neonatal stages.