Mutations in RHOT1 Disrupt Endoplasmic Reticulum–Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson's Disease

• DOI: 10.1089/ars.2018.7718
• Publication Date: 2019-07-15T07:19:00Z
• Authors: Dajana Grossmann; Clara Berenguer-E...; Marie Estelle Bellet; David Scheibner; Jill Bohler; Francois Massart; Doron Rapaport; Alexander Skupin; Aymeric Fouquier ...; Manu Sharma; Jenny Ghelfi; Aleksandar Raković; Peter Lichtner; Paul Antony; Enrico Glaab; Patrick May; Kai Stefan Dimmer; Julia Catherine F...; Anne Grünewald; Rejko Krüger
• Keywords: PINK1; Homeostasis; Calcium Signaling

Aims: The outer mitochondrial membrane protein Miro1 is a crucial player in dynamics and calcium homeostasis. Recent evidence indicated that mediates calcium-induced shape transition, which prerequisite for the initiation of mitophagy. Moreover, altered levels have emerged as shared feature monogenic sporadic Parkinson's disease (PD), but, so far, no disease-associated variants RHOT1 been identified. Here, we aim to explore genetic functional contribution mutations PD patient-derived cellular models. Results: For first time, describe heterozygous two patients (het c.815G>A; het c.1348C>T) identified phenotypes with reduced mass patient fibroblasts. Both led decreased endoplasmic reticulum-mitochondrial contact sites dyshomeostasis. As consequence, energy metabolism was impaired, turn caused increased Innovation Conclusion: Our study provides ROTH1 risk factor PD, further implicating homeostasis quality control.