Acronimo: INNER-BECN1

Titolo: New insights into myelin maintenance and peripheral nerve regeneration: the role of Beclin1

Codice Progetto: P2022Y2A3L

Responsabile scientifico per il DMM: Prof.ssa Matilde Cescon
Coordinatore: Università degli Studi di PADOVA - Prof.ssa Matilde Cescon

Partner-Unità di ricerca: Università degli Studi di TORINO

Bando: PRIN 2022 PRIN - Decreto Direttoriale n. 1409 del 14-09-2022
Durata: 30/11/2023 - 29/11/2025 (24 mesi)

Finanziamento progetto: € 239.711,00 – CUP C53D23007520001

 

Abstract del progetto

Traumatic and iatrogenic peripheral nerve injuries, as well as peripheral neuropathies, frequently result in lifelong disability due to suboptimal recovery, functional impairment and inflammation. Schwann cells (SCs), the supporting glial cells that produce myelin and sustain axonal metabolism, have a key role for successful nerve regeneration. Indeed, in response to nerve injury SCs display a particularly plastic behaviour, undergoing a de-differentiation program that is essential to orchestrate nerve regeneration, thus contributing to myelin clearance, immune cell recruitment and axonal regeneration by providing trophic factors and targeting innervation.

A deeper underlying myelin maintenance and SC-axon interaction in the adult,understanding of the molecular mechanisms would be important to target SC modulation with the idea of sustaining their repair phenotype in unmet clinical needs, in order to enhance and accelerate nerve regeneration in humans.

In our preliminary data, we describe a novel role for the protein Beclin-1 in myelination. The pathways it regulates, namely autophagy and endosomal trafficking, are essential during peripheral nerve development in SC maturation, in line with their implication in demyelinating diabetic and Charcot Marie Tooth peripheral neuropathies.

We demonstrated that the constitutive ablation of Beclin-1 in SCs triggers a severe demyelination that is accompanied by substantial alteration in the transcriptional program pointing to prompted mitosis at early stage, together with impaired nervous system development at later stages, with reactivation of pro-repair transcription factors. This points to autophagy and endosomal trafficking as promising targets able to impact on SC de-differentiation program upon injury.

Therefore, in this project we will test such processes in myelin maintenance during adulthood and on SC de-differentiation upon injury and in nerve regeneration. To do this, we will exploit: i) SC primary cultures, as a model of de-differentiating SC, in which Becn1 gene will be deleted to study mechanisms responsible for signalling pathways de-regulation; ii) an ad hoc produced inducible SC-specific Becn1 knockout mouse line, where the gene is ablated in response to tamoxifen, in order to monitor in vivo the impact of Beclin-1-regulated processes on myelin maintenance and on nerve regeneration and skeletal muscle innervation in adulthood.

Our major focus in the analyses will be on the autophagic and endosomal pathways as well as on the Neuregulin1-PI3K axis, expected to be altered in the absence of Beclin-1 and particularly relevant in SC-specific response to nerve injury. The successful achievement of the described aims will provide a better understanding of SC-directed processes in nerve repair and throw new light on candidate pathways relevant to pharmacologically handle nerve-injury outcome and long-term functional impairment in patients.