Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca2+ Influx but Only Modestly Influenced by Mitochondria
| Autor: | Laura Conforti, Andrea Loreto, Martin Gering, Michele Di Stefano |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Wallerian degeneration
medicine.medical_treatment Mitochondrion Biology General Biochemistry Genetics and Molecular Biology Amidohydrolases Mice Piperidines medicine Animals Nicotinamide-Nucleotide Adenylyltransferase Axon Fragmentation (cell biology) lcsh:QH301-705.5 Nicotinamide Mononucleotide Nicotinamide mononucleotide Armadillo Domain Proteins Ions Membrane Potential Mitochondrial Mice Knockout Acrylamides Nicotinamide-nucleotide adenylyltransferase Depolarization Anatomy medicine.disease Axons Mitochondria Cell biology Mice Inbred C57BL Cytoskeletal Proteins medicine.anatomical_structure nervous system lcsh:Biology (General) Calcium Axotomy Wallerian Degeneration |
| Zdroj: | Cell Reports, Vol 13, Iss 11, Pp 2539-2552 (2015) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.11.032 |
| Popis: | Axon injury leads to rapid depletion of NAD-biosynthetic enzyme NMNAT2 and high levels of its substrate, NMN. We proposed a key role for NMN in Wallerian degeneration but downstream events and their relationship to other mediators remain unclear. Here, we show, in vitro and in vivo, that axotomy leads to a late increase in intra-axonal Ca(2+), abolished by pharmacological or genetic reduction of NMN levels. NMN requires the pro-degenerative protein SARM1 to stimulate Ca(2+) influx and axon degeneration. While inhibition of NMN synthesis and SARM1 deletion block Ca(2+) rise and preserve axonal integrity, they fail to prevent early mitochondrial dynamic changes. Furthermore, depolarizing mitochondria does not alter the rate of Wallerian degeneration. These data reveal that NMN and SARM1 act in a common pathway culminating in intra-axonal Ca(2+) increase and fragmentation and dissociate mitochondrial dysfunctions from this pathway, elucidating which steps may be most effective as targets for therapy. |
| Databáze: | OpenAIRE |
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