[en] Mitochondrial markers help stratify Parkinson's disease (PD) patients. We use high-throughput blotting to quantify Miro1, Mfn2, and VDAC levels in fibroblasts, blood cells, and iPSC-derived neurons. Miro1 is specifically retained in PD cells but degraded in healthy ones after mitochondrial depolarization. We correlate Miro1 retention scores with pathogenic mutations, genetic background, age, and clinical data. This scalable assay and quantifiable score for mitochondrial-PD support biomarker development and pharmacological screening.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) Luxembourg Centre for Systems Biomedicine (LCSB): Molecular & Functional Neurobiology (Grünewald Group)
Disciplines :
Genetics & genetic processes Neurology
Author, co-author :
Drwesh, Layla; Department of Neurodegeneration, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
Merk, Daniel J; Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany
FERRANTE, Daniele ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
GORGOGIETAS, Vyron ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Gasser, Thomas; Department of Neurodegeneration, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Brockmann, Kathrin; Department of Neurodegeneration, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Centre Hospitalier de Luxembourg > Parkinson Research Clinic ; Transversal Translational Medicine > Luxembourg Institute of Health (LIH), Strassen
Wüst, Richard; University Hospital Tübingen, Center for Mental Health, Eberhard Karls University Tübingen, Tübingen, Germany
Gloeckner, Christian Johannes; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Fitzgerald, Julia C; Department of Neurodegeneration, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany. julia.fitzgerald@uni-tuebingen.de
A.F. MacAskill et al. GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons Mol. Cell Neurosci. 40 301 312 1:CAS:528:DC%2BD1MXit1OrtLk%3D 10.1016/j.mcn.2008.10.016 19103291
X. Guo et al. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses Neuron 47 379 393 1:CAS:528:DC%2BD2MXovFSjsLo%3D 10.1016/j.neuron.2005.06.027 16055062
A.F. MacAskill et al. Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses Neuron 61 541 555 1:CAS:528:DC%2BD1MXlt1KlsL8%3D 10.1016/j.neuron.2009.01.030 19249275 2670979
R. Bagur G. Hajnóczky Intracellular Ca2+ sensing: role in calcium homeostasis and signaling Mol. Cell 66 780 1:CAS:528:DC%2BC2sXhtVWrtrjI 10.1016/j.molcel.2017.05.028 28622523 5657234
X. Wang et al. PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility Cell 147 893 1:CAS:528:DC%2BC3MXhsVKgsLbP 10.1016/j.cell.2011.10.018 22078885 3261796
Barazzuol, L. et al. PINK1/parkin mediated mitophagy, Ca2+ Signalling, and ER-mitochondria contacts in Parkinson’s Disease. Int. J. Mol. Sci. 21, 1772 2020.
A. Weihofen et al. Pink1 forms a multiprotein complex with miro and Milton, linking Pink1 function to mitochondrial trafficking Biochemistry 48 2045 2052 1:CAS:528:DC%2BD1MXhvFGgsbs%3D 10.1021/bi8019178 19152501
Hsieh, C-H. et al. Supplemental information functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell19, 709–724 (2016).
Safiulina, D. et al. Miro proteins prime mitochondria for Parkin translocation and mitophagy. EMBO J.38, e33384 (2019).
Klosowiak, J. L. et al. Structural insights into Parkin substrate lysine targeting from minimal Miro substrates. Sci. Rep. 6, 33019 (2016).
Kontou, G. et al. Miro1-dependent mitochondrial dynamics in parvalbumin interneurons. Elife10, e65215 (2021).
C. Berenguer-Escuder et al. Variants in miro1 cause alterations of er-mitochondria contact sites in fibroblasts from Parkinson’s disease patients J. Clin. Med. 8 2226 1:CAS:528:DC%2BB3cXmslyqsr4%3D 10.3390/jcm8122226 31888276 6947516
D. Grossmann et al. Mutations in RHOT1 disrupt endoplasmic reticulum-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson’s disease Antioxid. Redox Signal 31 1213 1234 1:CAS:528:DC%2BC1MXhvF2hu7%2FL 10.1089/ars.2018.7718 31303019 6798875
A. Anvret et al. Genetic screening of the mitochondrial Rho GTPases MIRO1 and MIRO2 in Parkinson’s disease Open Neurol. J. 6 1 1:CAS:528:DC%2BC38Xmt1eisrY%3D 10.2174/1874205X01206010001 22496713 3322431
M. Saeed Genomic convergence of locus-based GWAS meta-analysis identifies AXIN1 as a novel Parkinson’s gene Immunogenetics 70 563 570 1:CAS:528:DC%2BC1cXhtFKgsbrF 10.1007/s00251-018-1068-0 29923028
M.A. Nalls et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-genome wide association study Lancet Neurol. 18 1091 1:CAS:528:DC%2BC1MXitFemsbbF 10.1016/S1474-4422(19)30320-5 31701892 8422160
M.T. Periñán et al. The role of RHOT1 and RHOT2 genetic variation on Parkinson disease risk and onset Neurobiol. Aging 97 144 10.1016/j.neurobiolaging.2020.07.003
Grossmann, D. et al. The emerging role of RHOT1/Miro1 in the pathogenesis of Parkinson’s disease. Front. Neurol.11, 587 (2020).
C.H. Hsieh et al. Miro1 marks Parkinson’s disease subset and miro1 reducer rescues neuron loss in Parkinson’s models Cell Metab. 30 1131 1140 1:CAS:528:DC%2BC1MXhvVylsbrJ 10.1016/j.cmet.2019.08.023 31564441 6893131
Nguyen, D. et al. Miro1 impairment in a parkinson’s At-risk cohort. Front. Mol. Neurosci. 14, 734273 (2021).
Zittlau, K. I. et al. Temporal analysis of protein ubiquitylation and phosphorylation during parkin-dependent mitophagy. Mol. Cell. Proteom.21, 100191 (2022).
U. Nguyen et al. The Simple WesternTM: a gel-free, blot-free, hands-free Western blotting reinvention Nat. Methods 8 v vi 10.1038/nmeth.f.353
G. Arena et al. Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson’s Disease Ann. Neurol. 96 133 149 1:CAS:528:DC%2BB2cXhtlSktLvI 10.1002/ana.26949 38767023
C.H. Hsieh et al. Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease Cell Stem Cell 19 709 724 1:CAS:528:DC%2BC28XhsVyktL%2FP 10.1016/j.stem.2016.08.002 27618216 5135570
S.J. Park R.A. Frake D.C. Rubinsztein Increased SORBS3 expression in brain ageing contributes to autophagic decline via YAP1-WWTR1/TAZ signaling Autophagy 19 943 944 1:CAS:528:DC%2BB38Xit1yjtrfF 10.1080/15548627.2022.2100106 35822241
P. Reinhardt et al. Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling PLoS One 8 59252 10.1371/journal.pone.0059252
Bus, C. et al. Human dopaminergic neurons lacking PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 Co-factors. iScience23, 101797 (2020).
López-Doménech. G. et al. Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response. EMBO J.40, 100715 (2021).
M. Kuhn Building predictive models in R using the caret package J. Stat. Softw. 28 1 26 10.18637/jss.v028.i05
S.W. Choi P.F. O’Reilly PRSice-2: Polygenic Risk Score software for biobank-scale data Gigascience 8 10.1093/gigascience/giz082 31307061 6629542 giz082
