PgmNr D1375: ER shaping protein REEP1 regulates neuronal lipid droplets in vivo.

Authors:
N. D'Elia 1 ; S. Gumeni 2 ; M. Fantin 2 ; A. Forgiarini 1 ; M. Corrà 2 ; A. Martinuzzi 2 ; G. Orso 1,2


Institutes
1) Institute of Pediatric Research, Padova, PD, IT; 2) Scientific Institute IRCCS Eugenio Medea, Conegliano, TV, IT.


Keyword: neural disorder

Abstract:

Defects in endoplasmic reticulum (ER) membrane shaping and its interactions to other organelles seem to be crucial mechanisms underlying Hereditary Spastic Paraplegia (HSP) neurodegeneration.

Here we report the analysis of a Drosophila model for HSP caused by mutations in the SPG31 gene, which are linked to autosomal dominant HSP. SPG31 codifies for REEP1, which is a transmembrane protein belonging to the TB2/Dp1/HVA22 family. REEP1 interaction with atlastin-1 (SPG3A) and spastin (SPG4), the other two major HSP linked proteins, has been demonstrated to modify ER architecture. The last evidence that both atlastin-1 and REEP1 play a role in lipid droplets (LDs) biology prompted us to investigate the in vivo role of REEP1 in ER membrane shaping and LDs biogenesis using Drosophila melanogaster as a model organism. We show that Drosophila REEP1 mutant flies present altered ER membrane morphology in neurons and reduced LDs number in both neuronal and non neuronal tissues. In addition, overexpression of wild type DREEP1 affects LDs number and size. Furthermore, we generated and in vivo expressed the mutated pathological form of DREEP1 p.P19R. The p.P19R missense mutation increases LDs size, reduces their number and modifies DREEP1 subcellular localization relocating it from ER to LDs membrane. Modification of LDs biogenesis is also associated to triglyceride levels perturbation in vivo, suggesting an altered lipid metabolism.

Our data demonstrate that REEP1 is involved in ER morphogenesis and LDs biogenesis/turnover in neuronal tissues. Our findings support and highlight the importance of lipid metabolism in neural functionality and the neurodegeneration mechanism of HSP disorder. Therefore, lipid metabolism can be considered as a novel HSP target towards which pharmacological efficient treatments could be developed.



Flybase Genetic Index:
1. FlyBase gene symbol: Reep1; FBgn: FBgn0261564