Flavonoid treatment restores impaired function
The fruitfly equivalent of human REEP1 protein, mutations in which are responsible for SPG31, causes detrimental modification to the architecture of the vital cell membrane known as endoplasmic reticulum in the fruitflies. This leads to impaired ability to fly and shortened lifespan. A flavonoid with strong antioxidant and neuroprotective activity, naringenin, restored the ability to fly and normal lifespan.
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.
SOURCE: Front Neurosci. 2019 Nov 19;13:1202. doi: 10.3389/fnins.2019.01202. eCollection 2019. PMID: 31803000 Copyright © 2019 Napoli, Gumeni, Forgiarini, Fantin, De Filippis, Panzeri, Vantaggiato and Orso.
Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes.
1 Scientific Institute, IRCCS Eugenio Medea, Laboratory of Molecular Biology, Bosisio Parini, Lecco, Italy.
2 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
3 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
4 Foundation Institute of Pediatric Research, “Città della Speranza”, Padova, Italy.