Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson's Disease Patients
Authors: Lena F Burbulla
Philip Seibler
Dajana Grossmann
Franҫois Massart
Paul Antony
Clara Berenguer-Escuder
Anne Grünewald
Sophie Imhoff
Rejko Krüger
Enrico Glaab
Joanne Trinh
Journal: Journal of clinical medicine (2019)
Discipline: CLINICAL MEDICINE
Keywords: Miro1; Parkinson´s disease; mitochondria-ER contact sites.
Affiliations: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4367 Belvaux, Luxembourg., Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany., Luxembourg Institute of Health (LIH), 1445 Strassen, Luxembourg., Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), 1460 Luxembourg, Luxembourg.

Abstract:  Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient-derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. 

Retracted: No

PubPeer comments:
 One of the panels in this paper (Figure 2D), is identical to another panel (Figure 2I) from another paper from the same group (Dajana Grossmann et al. Antioxid Redox Signal 2019 doi: 10.1089 ars.2018.7718.) ![file] , 
 #1 The authors have now issued a correction: https: www.liebertpub.com doi 10.1089 ars.2018.7718.correx Stating: In the December 1, 2019 issue of Antioxidants Redox Signaling (vol. 31, no. 16, 1213-1234) the article entitled u201cMutations in RHOT1 Disrupt Endoplasmic Reticulumu2013Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson s Diseaseu201d by Grossmann et al. requires correction. In Figure 2I, the microscopy image of control fibroblasts is not representative of the results shown in Figure 2H. The related microscopy image for the control in Figure 2I was erroneously chosen from another control cell line, not part of the study. The original Figure 2I is shown below: The online version has been corrected to reflect this. The authors apologize for this error. ,