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

Hanna Bayer; Kerstin Lang; Eva Buck; Julia Higelin; Lara Barteczko; Noemi Pasquarelli; Jasmin Sprissler; Tanja Lucas; Karlheinz Holzmann; Maria Demestre; Katrin S Lindenberg; Karin M Danzer; Tobias Boeckers; Albert C Ludolph; Luc Dupuis; Patrick Weydt; Anke Witting

doi:10.1016/j.nbd.2016.11.001

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

Neurobiol Dis. 2017 Jan;97(Pt A):36-45. doi: 10.1016/j.nbd.2016.11.001. Epub 2016 Nov 3.

Authors

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

Affiliations

¹ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
² Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
³ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
⁴ Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: [email protected].
⁵ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
⁶ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
⁷ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
⁸ Department of Gene Therapy, Ulm University, Ulm, DE 89081, Germany. Electronic address: [email protected].
⁹ Genomics Core Facility, Ulm University, Ulm, DE 89081, Germany. Electronic address: [email protected].
¹⁰ Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: [email protected].
¹¹ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
¹² Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
¹³ Institute of Anatomy and Cell Biology, Ulm University, Ulm, DE 89081, Germany. Electronic address: [email protected].
¹⁴ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].
¹⁵ INSERM U1118, F 67085, France; Université de Strasbourg, fédération de Médecine Translationnelle, F 67085, France. Electronic address: [email protected].
¹⁶ Department of Neurology, Ulm University, DE 89081, Germany; Department of Neurodegenerative Disorders and Gerontopsychiatry, University of Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
¹⁷ Department of Neurology, Ulm University, DE 89081, Germany. Electronic address: [email protected].

PMID: 27818323
DOI: 10.1016/j.nbd.2016.11.001

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.

Keywords: Amyotrophic lateral sclerosis; FUS; Lactate; Lou Gehrig disease; PGC-1α; SOD1.

Publication types

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

MeSH terms

Adipose Tissue, Brown / metabolism
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism*
Animals
Brain / metabolism*
Cell Line
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells / metabolism
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Skeletal / metabolism
Mutation
Neurons / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
Protein Isoforms
RNA, Messenger / metabolism
RNA-Binding Protein FUS / genetics*
RNA-Binding Protein FUS / metabolism
Rats
Superoxide Dismutase-1 / genetics*
Superoxide Dismutase-1 / metabolism

Substances

FUS protein, human
PPARGC1A protein, human
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Ppargc1a protein, rat
Protein Isoforms
RNA, Messenger
RNA-Binding Protein FUS
SOD1 protein, human
Superoxide Dismutase-1