Medical Scientist-Programm 2026

Titel: "Impact of ER shaping disorders on ER contact sites: A comparative analysis of Reep1 and Reep2 KO mice"

Zusammenfassung:
Variants in genes encoding endoplasmic reticulum (ER)-resident membrane-shaping proteins such REEP1 and REEP2 are associated with ER structural abnormalities and axonal degeneration. REEP1 and REEP2 share a high homology and show overlapping expression. Despite this clear genetic link, the mechanisms by which ER morphological defects ultimately lead to neurodegeneration remain poorly understood. Building on our data showing that mutations in REEP1 alter ER architecture and are accompanied by peroxisomal and mitochondrial defects, we hypothesize that these occur secondary to changes in ER contact sites (ERCs). ERCs are regions where the ER closely apposes other organelles to allow rapid, localized exchange of lipids and calcium. They also act as signaling hubs that regulate organelle dynamics, metabolism, stress responses, and cell fate. To test our hypothesis, we propose a comparative analysis of Reep1 knockout (KO), Reep2 KO, and Reep1/Reep2 double KO (dKO) mice. This approach will allow us to determine whether ER abnormalities observed in Reep1 KO mice are exacerbated by concomitant loss of Reep2 and to assess the resulting impact on ERCs. We will then assess, how defective ERCs affect the homeostasis of other organelles. Disruption of these processes may promote ER stress, impair organelle function, and lead to the accumulation of toxic proteins, thereby contributing to the progression of axon degeneration.