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

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

来源：Neurobiology of Disease, 2017, 97: 36-45.

DOI：10.1016/j.nbd.2016.11.001

• Amyotrophic lateral sclerosis
• Lou Gehrig disease
• PGC-1 alpha
• Lactate
• FUS
• SOD1

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)-1 alpha (PGC-1 alpha).
Methods: We analyzed the expression of PGC-1 alpha isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1 alpha signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUSMS mutations.
Results: Mutations in SOD1 and FUS/ILS 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-1 alpha isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1 alpha deficient neurons. The lactate-induced CNS-specific PGC-1 alpha signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUSAIS mutations.
Conclusion: ALS mutations increase the canonical PGC-1 alpha system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1 alpha system directly linking brain metabolism and neuroprotection. Changes in the PGC-1 alpha system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.

• 出版日期2017-1