Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach

Wonphorn Kandhavivorn; Hannes Glaß; Thomas Herrmannsdörfer; Tobias M Böckers; Marc Uhlarz; Jonas Gronemann; Richard H W Funk; Jens Pietzsch; Arun Pal; Andreas Hermann

doi:10.3390/cells12111502

Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach

Cells. 2023 May 29;12(11):1502. doi: 10.3390/cells12111502.

Authors

Wonphorn Kandhavivorn^{1

2}, Hannes Glaß^{3

4}, Thomas Herrmannsdörfer¹, Tobias M Böckers^{5

6}, Marc Uhlarz¹, Jonas Gronemann¹, Richard H W Funk^{2

7}, Jens Pietzsch^{8

9}, Arun Pal^{1

3}, Andreas Hermann^{3

4

10

11}

Affiliations

¹ Dresden High Magnetic Field Laboratory (HLD-EMFL), Helmholtz-Zentrum Dresden-Rossendorf, D-01328 Dresden, Germany.
² Institute of Anatomy, Technische Universität Dresden, D-01307 Dresden, Germany.
³ Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, D-01307 Dresden, Germany.
⁴ Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, D-18147 Rostock, Germany.
⁵ Institute of Anatomy and Cell Biology, University of Ulm, D-89081 Ulm, Germany.
⁶ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Ulm, D-89081 Ulm, Germany.
⁷ Dresden International University, D-01067 Dresden, Germany.
⁸ Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, D-01328 Dresden, Germany.
⁹ Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, D-01069 Dresden, Germany.
¹⁰ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, D-18147 Rostock, Germany.
¹¹ Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, D-18147 Rostock, Germany.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range trafficking routes for organelles, cargo, mRNA and secretion with a high energy effort to serve crucial neuronal functions. Impaired intracellular pathways implicated in ALS pathology comprise RNA metabolism, cytoplasmic protein aggregation, cytoskeletal integrity for organelle trafficking and maintenance of mitochondrial morphology and function, cumulatively leading to neurodegeneration. Current drug treatments only have marginal effects on survival, thereby calling for alternative ALS therapies. Exposure to magnetic fields, e.g., transcranial magnetic stimulations (TMS) on the central nervous system (CNS), has been broadly explored over the past 20 years to investigate and improve physical and mental activities through stimulated excitability as well as neuronal plasticity. However, studies of magnetic treatments on the peripheral nervous system are still scarce. Thus, we investigated the therapeutic potential of low frequency alternating current magnetic fields on cultured spinal motoneurons derived from induced pluripotent stem cells of FUS-ALS patients and healthy persons. We report a remarkable restoration induced by magnetic stimulation on axonal trafficking of mitochondria and lysosomes and axonal regenerative sprouting after axotomy in FUS-ALS in vitro without obvious harmful effects on diseased and healthy neurons. These beneficial effects seem to derive from improved microtubule integrity. Thus, our study suggests the therapeutic potential of magnetic stimulations in ALS, which awaits further exploration and validation in future long-term in vivo studies.

Keywords: AC electromagnetic stimulation; amyotrophic lateral sclerosis; axonal organelle trafficking; axonal regeneration; axonal sprouting; axonopathy; induced pluripotent stem cells; microtubules stabilization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Axons / metabolism
Humans
Magnetic Fields
Motor Neurons / pathology
Organelles / metabolism
RNA-Binding Protein FUS / genetics
RNA-Binding Protein FUS / metabolism

Substances

FUS protein, human
RNA-Binding Protein FUS

Grants and funding

This work was supported, in part, by the TG 70 funding of the European Regional Development Fund (ERDF) via the Saxonian State Ministry of Science and Culture (SMWK), TU-Dresden and Sächsische Aufbaubank (SAB). Specifically, we are very grateful that we have received considerable support for our project (funding reference number 100533543) from the ERDF and from tax funds based on the budget passed by the Saxon State Parliament. A.H. is supported by the Hermann and Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband.