Hanna Bayer1, Kerstin Lang2, Eva Buck3, Julia Higelin4, Lara Barteczko5, Noemi Pasquarelli6, Jasmin Sprissler7, Tanja Lucas8, Karlheinz Holzmann9, Maria Demestre10, Katrin S Lindenberg11, Karin M Danzer12, Tobias Boeckers13, Albert C Ludolph14, Luc Dupuis15, Patrick Weydt16, Anke Witting17. 1. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: hanna.bayer@uni-ulm.de. 2. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Kerstin.lang@uni-ulm.de. 3. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: eva.buck@uni-ulm.de. 4. Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: Julia.higelin@uni-ulm.de. 5. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Lara.barteczko@uni-ulm.de. 6. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Noemi.pasquarelli@uni-ulm.de. 7. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Jasmin.sprissler@uni-ulm.de. 8. Department of Gene Therapy, Ulm University, Ulm, DE 89081, Germany. Electronic address: Tanjalucas@web.de. 9. Genomics Core Facility, Ulm University, Ulm, DE 89081, Germany. Electronic address: karlheinz.holzmann@uni-ulm.de. 10. Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: maria.demestre@uni-ulm.de. 11. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: katrin.lindenberg@uni-ulm.de. 12. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: karin.danzer@uni-ulm.de. 13. Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: tobias.boeckers@uni-ulm.de. 14. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: albert.ludolph@uni-ulm.de. 15. INSERM U1118, F 67085, France; Université de Strasbourg, fédération de Médecine Translationnelle, F 67085, France. Electronic address: ldupuis@neuro-cnrs.unistra.fr. 16. Department of Neurology, Ulm University, DE 89081, Germany; Department of Neurodegenerative Disorders and Gerontopsychiatry, University of Bonn, 53127 Bonn, Germany. Electronic address: patrick.weydt@uni-bonn.de. 17. Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: anke.witting@uni-ulm.de.
Abstract
BACKGROUND: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). METHODS: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations. RESULTS: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations. CONCLUSION: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration. Copyright Â
BACKGROUND: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). METHODS: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALSpatients harboring two different frame-shift FUS/TLS mutations. RESULTS: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALSpatients harboring two different frame-shift FUS/TLS mutations. CONCLUSION:ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration. Copyright Â
Authors: Anika M Helferich; Sarah J Brockmann; Jörg Reinders; Dhruva Deshpande; Karlheinz Holzmann; David Brenner; Peter M Andersen; Susanne Petri; Dietmar R Thal; Jens Michaelis; Markus Otto; Steffen Just; Albert C Ludolph; Karin M Danzer; Axel Freischmidt; Jochen H Weishaupt Journal: Cell Mol Life Sci Date: 2018-07-20 Impact factor: 9.261
Authors: Eva Buck; Hanna Bayer; Katrin S Lindenberg; Johannes Hanselmann; Noemi Pasquarelli; Albert C Ludolph; Patrick Weydt; Anke Witting Journal: Front Mol Neurosci Date: 2017-05-26 Impact factor: 5.639
Authors: L J McMeekin; A F Bartley; A S Bohannon; E W Adlaf; T van Groen; S M Boas; S N Fox; P J Detloff; D K Crossman; L S Overstreet-Wadiche; J J Hablitz; L E Dobrunz; R M Cowell Journal: Neuroscience Date: 2020-03-25 Impact factor: 3.590
Authors: J B Delaye; D Lanznaster; C Veyrat-Durebex; A Fontaine; G Bacle; A Lefevre; R Hergesheimer; J C Lecron; P Vourc'h; C R Andres; F Maillot; P Corcia; P Emond; H Blasco Journal: Neurotherapeutics Date: 2020-10-06 Impact factor: 7.620