Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes.

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

doi:10.3389/fnins.2019.01202

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.

Highlights

Receptor expression-enhancing protein 1 (REEP1) is an endoplasmic reticulum (ER) resident protein involved in the SPG31 form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder affecting motoneurons
We explored the role of ReepA in ER homeostasis by investigating the consequences of its loss
The function of REEP homologs in cellular stress has been previously investigated by different groups: HVA22, the plant homolog gene of REEP1, is required to counteract stressful situations by inhibiting the activation of programed cell death in plants (Chen et al, 2002); Drosophila ReepA downregulation enhances Tau aggregates, whereas its overexpression results protective, suggesting that ReepA is required to confer stress resistance against the accumulation of unfolded proteins induced by TM (Appocher et al, 2014); DNA damage in human cells triggers tubular ER extension via the p53-mediated expression of REEP1/2 and EI24, and this facilitates contacts between ER and mitochondria (Zheng et al, 2018)

Summary

Introduction

Receptor expression-enhancing protein 1 (REEP1) is an endoplasmic reticulum (ER) resident protein involved in the SPG31 form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder affecting motoneurons. ER architecture is created and maintained thanks to a continuous process of membrane remodeling, governed by homotypic fusion events, tubulation, and curvature rearrangements. REEP1 and Reticulon 2 are two of the main ER-shaping proteins involved in HSP (in SPG31 and SPG12 respectively), and due to their particular topology, are supposed to induce high membrane curvature of the ER, a process facilitated by cytoskeleton changes (Park et al, 2010; Beetz et al, 2013; Wang and Rapoport, 2019). Spastin, an ATPase protein mutated in 40% of HSP patients, is involved in the disassembly and remodeling of neuronal microtubules and participates in the maintenance of ER integrity together with REEP1, Atlastin and Reticulon 2 (Evans et al, 2006; Sanderson et al, 2006)

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Results

Conclusion