English
Institut für Molekulare Medizin Mainz
AG Methner
Research
We study neurodegenerative diseases such as Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Charcot-Marie-Tooth (CMT) disease using cell lines, primary neuronal cultures, patient-derived neurons, and in vivo animal models including mice and flies. Our focus is on organelle dysfunction, particularly mitochondrial dysfunction, ER-mitochondria crosstalk, and ferroptosis. Specifically, we investigate:
Projects
Charcot-Marie-Tooth (CMT) Disease: An inherited peripheral neuropathy causing muscle weakness and sensory loss, primarily in the limbs. Mutations in mitochondrial proteins like MFN2 or GDAP1 cause CMT. Our research indicates that GDAP1 mutations lead to ferroptotic neuronal degeneration and a block in the use of pyruvate leading to increased fatty acid oxidation. We are exploring therapeutic options using a fly model of Gdap1 deficiency and patient-derived motor neurons.
Parkinson's Disease (PD): A progressive disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. PD is caused by impaired mitochondrial quality control, increased iron levels, oxidative stress, and lipid peroxidation. We study altered iron metabolism and its interaction with oxidative stress, calcium signaling, and mitochondrial quality control using patient-derived neurons and fly models of familial PD. In a project funded by the DFG within the Priority program SPP2453 “Integration of mitochondria into the cellular proteostasis network”, we study the role of mitochondria-derived vesicles in dysfunctional mitochondrial protein import.
Amyotrophic Lateral Sclerosis (ALS): Marked by the degeneration of motor neurons, leading to muscle atrophy and paralysis. TDP-43 protein aggregation is a key pathological feature. We aim to develop a system to induce cellular aggregation via light induction, mimicking ALS models, to study metabolic impacts and neuronal degeneration mechanisms. This project is funded by the DFG as part of the collaborative research center SFB1551 “Polymer concepts in cellular functions”. Another project focuses on endosome-mitochondria contacts in ALS caused by Alsin mutation.
Autism Spectrum Disorder (ASD): A psychiatric disorder with highly heterogeneous presentations affecting behavior and communication. Mutations in SHANK3 and FMR1 genes, involved in synaptic activity, elevate the risk of ASD. We investigate mitochondrial dysfunction and redox modifications of synaptic proteins in ASD mouse models in collaboration with Michael Schmeisser’s lab, aiming to identify new treatments.
TMBIM Family: We focus on pH-dependent calcium channels in intracellular membranes, particularly TMBIM5, identified as a mitochondrial Calcium-Proton exchanger. A TMBIM5 loss-of-function mouse model shows skeletal myopathy. We continue to study TMBIM5 function using mouse, fly, and fish models.
In summary, the laboratory integrates diverse expertise and innovative techniques to advance our understanding of neurodegenerative diseases and identify potential therapeutic targets.
Selected Publications
Bueno D, Narayan Dey P, Schacht T, Wolf C, Wüllner V, Morpurgo E, Rojas-Charry L, Sessinghaus L, Leukel P, Sommer C, Radyushkin K, Florin L, Baumgart J, Stamm P, Daiber A, Horta G, Nardi L, Vasic V, Schmeisser MJ, Hellwig A, Oskamp A, Bauer A, Anand R, Reichert AS, Ritz S, Nocera G, Jacob C, Peper J, Silies M, Frauenknecht KBM, Schäfer MKE, Methner A. NECAB2 is an endosomal protein important for striatal function. Free Radic Biol Med [Internet]. 2023 Sep 16; Available from: dx.doi.org/10.1016/j.freeradbiomed.2023.09.003
Zhang L, Dietsche F, Seitaj B, Rojas-Charry L, Latchman N, Tomar D, Wüst RC, Nickel A, Frauenknecht KB, Schoser B, Schumann S, Schmeisser MJ, Vom Berg J, Buch T, Finger S, Wenzel P, Maack C, Elrod JW, Parys JB, Bultynck G, Methner A. TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy. Life Sci Alliance. 2022 Oct;5(10):e202201478.
van der Kooij MA, Rojas-Charry L, Givehchi M, Wolf C, Bueno D, Arndt S, Tenzer S, Mattioni L, Treccani G, Hasch A, Schmeisser MJ, Vianello C, Giacomello M, Methner A. Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels. J Mol Med [Internet]. 2022 Aug 9; Available from: dx.doi.org/10.1007/s00109-022-02235-x
Wolf C, Pouya A, Bitar S, Pfeiffer A, Bueno D, Rojas-Charry L, Arndt S, Gomez-Zepeda D, Tenzer S, Bello FD, Vianello C, Ritz S, Schwirz J, Dobrindt K, Peitz M, Hanschmann EM, Mencke P, Boussaad I, Silies M, Brüstle O, Giacomello M, Krüger R, Methner A. GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton. Commun Biol. 2022 Jun 3;5(1):541.
Rojas-Charry L, Nardi L, Methner A, Schmeisser MJ. Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders. J Mol Med. 2021 Feb;99(2):161–78.
Seitaj B, Maull F, Zhang L, Wüllner V, Wolf C, Schippers P, La Rovere R, Distler U, Tenzer S, Parys JB, Bultynck G, Methner A. Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery. Cells [Internet]. 2020 Sep 23;9(10). Available from: dx.doi.org/10.3390/cells9102147
Philippaert K, Roden M, Lisak D, Bueno D, Jelenik T, Radyushkin K, Schacht T, Mesuere M, Wüllner V, Herrmann AK, Baumgart J, Vennekens R, Methner A. Bax inhibitor-1 deficiency leads to obesity by increasing Ca2+-dependent insulin secretion. J Mol Med. 2020 Jun;98(6):849–62.
Herrmann AK, Wüllner V, Moos S, Graf J, Chen J, Kieseier B, Kurschus FC, Albrecht P, Vangheluwe P, Methner A. Dimethyl fumarate alters intracellular Ca2+ handling in immune cells by redox-mediated pleiotropic effects. Free Radic Biol Med. 2019 Sep;141:338–47.
Arnoux I, Willam M, Griesche N, Krummeich J, Watari H, Offermann N, Weber S, Narayan Dey P, Chen C, Monteiro O, Buettner S, Meyer K, Bano D, Radyushkin K, Langston R, Lambert JJ, Wanker E, Methner A, Krauss S, Schweiger S, Stroh A. Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease. Elife [Internet]. 2018 Sep 4;7. Available from: dx.doi.org/10.7554/eLife.38744
Jörg M, Plehn JE, Kristen M, Lander M, Walz L, Lietz C, Wijns J, Pichot F, Rojas-Charry L, Wirtz Martin KM, Ruffini N, Kreim N, Gerber S, Motorin Y, Endres K, Rossmanith W, Methner A, Helm M, Friedland K. N1-methylation of adenosine (m1A) in ND5 mRNA leads to complex I dysfunction in Alzheimer’s disease. Mol Psychiatry [Internet]. 2024 Jan 29; Available from: http://dx.doi.org/10.1038/s41380-024-02421-y
Complete list of my published work in My Bibliography
www.ncbi.nlm.nih.gov/myncbi/axel.methner.1/bibliography/public/
Funding
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The work in our research group is supported by the German Research Foundation (DFG).
Lab Members
Dr. Li Zhang, Postdoc
Dr. Liliana Rojas-Charry, Postdoc
Sara Bitar, PhD student
Felix Schmidt, PhD student
Ermis Papakonstantinou, PhD student
Mahdi Jahed Armaghani, incoming PhD student
Fatih Yasir, MD student
Yasminn Akele, student help