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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.01202

Naringenin ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-linked phenotypes

  • 1Eugenio Medea (IRCCS), Italy
  • 2Division of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Greece
  • 3University of Padova, Italy
  • 4Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Italy

Defects in the endoplasmic reticulum (ER) membrane shaping and the interactions with other organelles seem to be a crucial mechanism underlying Hereditary Spastic Paraplegia (HSP) neurodegeneration. REEP1, a transmembrane protein belonging to TB2/HVA22 family, is implicated in SPG31, an autosomal dominant form of HSP, and its interaction with Atlastin/SPG3A and Spastin/SPG4, the other two major HSP linked proteins, has been demonstrated to play a crucial role in modifying ER architecture. In addition, the Drosophila ortholog of REEP1, named ReepA, has been found to regulate the response to ER neuronal stress. Herein we investigated the role of ReepA in ER morphology and stress response. ReepA is upregulated under stress conditions and ageing. Our data show that ReepA triggers a selective activation of Ire1 and Atf6 branches of Unfolded Protein Response (UPR) and modifies ER morphology. Drosophila lacking ReepA showed Atf6 and Ire1 activation, expansion of ER sheet-like structures, locomotor dysfunction and shortened lifespan. Furthermore, we found that naringenin, a flavonoid that possesses strong antioxidant and neuroprotective activity, can rescue the cellular phenotypes, the lifespan and locomotor disability associated with ReepA loss of function. Our data highlight the importance of ER homeostasis in nervous system functionality and HSP neurodegenerative mechanisms, opening new opportunities for HSP treatment.

Keywords: Endoplasmic Reticulum, hereditary spastic paraplegia, Naringenin, REEP1, ReepA, upr

Received: 31 Jul 2019; Accepted: 23 Oct 2019.

Copyright: © 2019 Napoli, Gumeni, Forgiarini, Fantin, De Filippis, Panzeri, Vantaggiato and Orso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Genny Orso, University of Padova, Padova, 35122, Veneto, Italy, genny7575@gmail.com