Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes

Barbara Napoli, Sentiljana Gumeni, Alessia Forgiarini, Marianna Fantin, Concetta De Filippis, Elena Panzeri, Chiara Vantaggiato, Genny Orso

Research output: Contribution to journalArticle

Abstract

Defects in the endoplasmic reticulum (ER) membrane shaping and interaction 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 aging. 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.

Original languageEnglish
Article number1202
Number of pages15
JournalFrontiers in Neuroscience
Volume13
DOIs
Publication statusPublished - Nov 19 2019

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Keywords

  • endoplasmic reticulum
  • hereditary spastic paraplegia
  • naringenin
  • REEP1
  • ReepA
  • UPR

ASJC Scopus subject areas

  • Neuroscience(all)

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