ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues.
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).



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.



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.



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.
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: hanna.bayer@uni-ulm.de.
Hanna
H
Bayer
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Kerstin.lang@uni-ulm.de.
Kerstin
K
Lang
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: eva.buck@uni-ulm.de.
Eva
E
Buck
Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: Julia.higelin@uni-ulm.de.
Julia
J
Higelin
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Lara.barteczko@uni-ulm.de.
Lara
L
Barteczko
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Noemi.pasquarelli@uni-ulm.de.
Noemi
N
Pasquarelli
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: Jasmin.sprissler@uni-ulm.de.
Jasmin
J
Sprissler
Department of Gene Therapy, Ulm University, Ulm, DE 89081, Germany. Electronic address: Tanjalucas@web.de.
Tanja
T
Lucas
Genomics Core Facility, Ulm University, Ulm, DE 89081, Germany. Electronic address: karlheinz.holzmann@uni-ulm.de.
Karlheinz
K
Holzmann
Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: maria.demestre@uni-ulm.de.
Maria
M
Demestre
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: katrin.lindenberg@uni-ulm.de.
Katrin S
KS
Lindenberg
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: karin.danzer@uni-ulm.de.
Karin M
KM
Danzer
Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: tobias.boeckers@uni-ulm.de.
Tobias
T
Boeckers
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: albert.ludolph@uni-ulm.de.
Albert C
AC
Ludolph
INSERM U1118, F 67085, France; Université de Strasbourg, fédération de Médecine Translationnelle, F 67085, France. Electronic address: ldupuis@neuro-cnrs.unistra.fr.
Luc
L
Dupuis
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.
Patrick
P
Weydt
Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: anke.witting@uni-ulm.de.
Anke
A
Witting
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism
C000599550:FUS protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D020033:Protein Isoforms; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
Amyotrophic lateral sclerosis; FUS; Lactate; Lou Gehrig disease; PGC-1α; SOD1