Hjem
Institutt for biomedisin

BBB Seminar: Michael Coleman

Hovedinnhold

Regulation of axon degeneration in injury and disease by delivery of Nmnat enzymes 

Michael Coleman,
Laboratory of Molecular Signaling, The Babraham Institute, Cambridge, UK

Early loss of axons and synapses is common to many neurodegenerative diseases and a major contributor to symptoms. Axonal transport defects are widespread and in some cases are known to cause axon degeneration. These can be modelled by axon injury, which totally prevents delivery of cargoes from the cell body to trigger Wallerian degeneration.

Intriguingly, a single protein is sufficient to delay the Wallerian degeneration by tenfold after axon injury. This is the ‘slow Wallerian degeneration’ protein (WldS), an aberrant protein that arose in a healthy mutant mouse and combines sequences from nicotinamide mononucleotide adenylyltransferase Nmnat1 and ubiquitin ligase Ube4b. Mislocalization or overexpression of Nmnat1 or Nmnat3 respectively have similar protective effects.

In contrast, depletion of an endogenous Nmnat isoform causes Wallerian-like degeneration of neurites in primary culture even without injury. WldS prevents this degeneration, probably by compensating for loss of Nmnat2 in an enzyme-dependent manner. However, the Nmnat function that promotes axon survival may not be NAD+ synthesis. Nmnat2 is abundant in the Golgi but live imaging shows it is also rapidly and bidirectionally transported along neurites. Our data suggest it is targeted to vesicular structures by palmitoylation, where it frequently comigrates with other Golgi-derived proteins but not with mitochondria.

In healthy axons, constant delivery of this essential protein seems to balance its degradation by the ubiquitin proteasome system, maintaining its level above the threshold needed for axon survival. When axonal transport or neuronal metabolism is reduced, we propose that failure to replace natural turnover of Nmnat2 limits axon survival.

Chair: Mathias Ziegler , Department of Molecular Biology