Molecular basis of axon longevity
If you are over 20, you will lose fifty thousand synapses while reading this sentence. Although the adult brain retains synapse plasticity, new synapses can only form if the underlying axons and dendrites remain.
Unfortunately, we also lose over two miles of myelinated axon fibres every day, a 45% reduction by the age of 80. Despite the survival of most cell bodies, the lack of CNS axon regeneration means this is a largely irreversible loss. Limiting axon loss is essential for healthy ageing.
The consequences of age-related axon loss arise when numbers fall below a threshold level. We compensate for cognitive decline in middle age by remodeling and using our brains differently (www.cam-can.com).
However, metabolic, environmental or genetic factors accelerate axon loss in some individuals, and in all of us the risks of age-related disorders such as dementia increase because even if mechanisms differ the losses due to ageing and disease are additive.
Mechanisms of axon loss are poorly understood but experimental axon injury, which causes Wallerian degeneration of the distal axon, is a particularly informative model (Figure, top right). Axons must traffic proteins, organelles and other essential cargoes over intracellular distances vastly exceeding other cell types. This axonal transport process (see Movie) takes days to reach distal axons that can be up to one meter from the cell body. Efficient axonal transport must continue for decades but the transection model shows that distal axons die within hours if it fails.
Axonal transport halves during normal ageing. Our live imaging confirms this does not simply reflect reduced axon number but occurs at the level of individual axons (Gilley et al, Neurobiol Ageing 2012). The next step is to test whether this transport decline causes age-related axon loss and to study downstream and upstream mechanisms.
Two neuroprotective mutations that robustly preserve injured axons enable this work (Figure). First, the slow Wallerian degeneration protein, an aberrant fusion protein that we identified (Mack et al, Nat Neurosci 2001), promotes axon survival through a gain-of-function mechanism that implicates NAD and related metabolites. Candidates for steps downstream of NAD metabolism include autophagy and sirtuins, which influence ageing at organism level. Second, our collaborator Marc Freeman (UMass Med) has identified a novel protein in Drosophila that is actually required for axons to degenerate, as loss-of-function mutations robustly phenocopy WldS. Together, we have shown that this strong axon protection in conserved in mammals.
These exciting axon survival proteins, both identified using transection models, can now be studied in the context of ageing nerves. Moreover, understanding how they work is the key to other events that may influence age-related axon loss. For example, we find that WldS mislocalises an NAD synthetic enzyme into axons where it substitutes for the endogenous axonal enzyme, Nmnat2. Nmnat2 is essential for axon survival and has a short half-life, so the rapid decline in its level distal to an axon transection leads to axon degeneration. In ageing, we suggest there is a double hit of an age-related decline in Nmnat2 transport combined with Nmnat2 turnover during transport, and that together these deprive distal axons of the Nmnat2 they need to survive. In contrast, WldS is a stable protein with the same enzyme activity. This enables it to substitute for prolonged periods after transection and to survive the long journey to distal axons. Current studies to test this model include quantitative live imaging of axonal transport in peripheral nerves from ageing Nmnat2-Venus transgenic mice.
Updated 8 May, 2012