Professional Education


  • Bachelor degree, School of Biology and Biotechnology University of Bicocca, Milan, Italy (2008)
  • Master degree, Medical Biotechnology, School of Medicine and Surgery, San Raffaele Scientific Institute, Milan, Italy, Biotechnology (2011)
  • Doctor of Philosophy, S.U.N.Y. State University at Buffalo (2015)

Stanford Advisors


All Publications


  • Calcineurin activity is increased in Charcot-Marie-Tooth 1B demyelinating neuropathy. The Journal of neuroscience : the official journal of the Society for Neuroscience Sidoli, M., Reed, C. B., Scapin, C., Paez, P., Cavener, D. R., Kaufman, R. J., D'Antonio, M., Feltri, M. L., Wrabetz, L. 2021

    Abstract

    Schwann cells produce a considerable amount of lipids and proteins to form myelin in the peripheral nervous system (PNS). For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and mice. Misfolded P0S63del accumulates in the endoplasmic reticulum (ER) of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/PerkSCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with Calcineurin/NFATc4 pro-myelinating pathway. Using mouse genetics including females and males in our experimental setting, we show that PERK and Calcineurin interact in P0S63del nerves and that Calcineurin activity and NFATc4 nuclear localization are increased in S63del Schwann cells, without altering EGR2/KROX20 expression. Moreover, genetic manipulation of the Calcineurin subunits appears to be either protective or toxic in S63del in a context dependent manner, suggesting that Schwann cells are highly sensitive to alterations of Calcineurin activity.SIGNIFICANCE STATEMENT:Our work shows a novel activity and function for Calcineurin in Schwann cells in the context of ER stress. Schwann cells expressing the S63del mutation in P0 protein induce the unfolded protein response and upregulate Calcineurin activity. Calcineurin interacts with the ER stress transducer PERK but the relationship between the UPR and Calcineurin in Schwann cells is unclear. Here we propose a protective role for Calcineurin in S63del neuropathy although Schwann cells appear to be very sensitive to its regulation. The paper uncovers a new important role for Calcineurin in a demyelinating diseases.

    View details for DOI 10.1523/JNEUROSCI.2384-20.2021

    View details for PubMedID 33879538

  • Deletion of Calcineurin in Schwann Cells Does Not Affect Developmental Myelination, But Reduces Autophagy and Delays Myelin Clearance after Peripheral Nerve Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience Reed, C. B., Frick, L. R., Weaver, A., Sidoli, M., Schlant, E., Feltri, M. L., Wrabetz, L. 2020

    Abstract

    In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating an SC conditional KO of calcineurin B (CnBscko), we assessed the effects of CnB ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnBscko mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnBscko mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury.Significance Statement:Our data offer a novel mechanism for activation of autophagy after peripheral nerve injury. Efficient clearance of myelin after injury by Schwann cells is important for axonal regrowth and remyelination, which is one reason why the PNS is significantly better at recovery compared with the CNS. Improved understanding of myelin clearance allows for the identification of pathways that are potentially accessible to increase myelin clearance and improve remyelination and recovery. Finally, this paper clarifies the role of calcineurin in Schwann cells and myelination.

    View details for DOI 10.1523/JNEUROSCI.0951-20.2020

    View details for PubMedID 32641402

  • The role of calcineurin in Schwann cells and myelination Reed, C., Sidoli, M., Feltri, M., Wrabetz, L. WILEY. 2018: 285