Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes
| Autor: | Concetta De Filippis, Sentiljana Gumeni, Marianna Fantin, Genny Orso, Chiara Vantaggiato, Barbara Napoli, Elena Panzeri, Alessia Forgiarini |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Atlastin Hereditary spastic paraplegia naringenin UPR Biology Spastin Neuroprotection lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine medicine hereditary spastic paraplegia lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Original Research ATF6 General Neuroscience Endoplasmic reticulum Neurodegeneration medicine.disease 3. Good health Cell biology endoplasmic reticulum 030104 developmental biology Unfolded protein response REEP1 ReepA 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Frontiers in Neuroscience Frontiers in Neuroscience, Vol 13 (2019) |
| ISSN: | 1662-453X |
| DOI: | 10.3389/fnins.2019.01202 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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