Abstract
Dopamine neurons of the substantia nigra pars compacta (SNc) are uniquely sensitive to degeneration in Parkinson's disease (PD) and its models. Although a variety of molecular characteristics have been proposed to underlie this sensitivity, one possible contributory factor is their massive, unmyelinated axonal arbor that is orders of magnitude larger than other neuronal types. We suggest that this puts them under such a high energy demand that any stressor that perturbs energy production leads to energy demand exceeding supply and subsequent cell death. One prediction of this hypothesis is that those dopamine neurons that are selectively vulnerable in PD will have a higher energy cost than those that are less vulnerable. We show here, through the use of a biology-based computational model of the axons of individual dopamine neurons, that the energy cost of axon potential propagation and recovery of the membrane potential increases with the size and complexity of the axonal arbor according to a power law. Thus SNc dopamine neurons, particularly in humans, whose axons we estimate to give rise to more than 1 million synapses and have a total length exceeding 4 m, are at a distinct disadvantage with respect to energy balance which may be a factor in their selective vulnerability in PD.
Highlights
The selective degeneration of dopamine neurons of the substantia nigra pars compacta (SNc) is responsible for the principal motor symptoms of Parkinson’s disease (PD)
We constructed axonal trees representing dopamine neurons that are especially susceptible in PD and those that are less susceptible, but note that we did not take into account possible electrophysiological differences between the types of neurons
These features included those that are considered to be typical of SNc dopamine neurons, such as a wide action potentials (AP) (Richards et al, 1997), autonomous pacemaking activity (Grace and Bunney, 1984b), depolarization block in response to positive current (Blythe et al, 2009; Tucker et al, 2012), and a hyperpolarization sag in response to negative current injection (Neuhoff et al, 2002; Figure 2, see “Materials and Methods”)
Summary
The selective degeneration of dopamine neurons of the substantia nigra pars compacta (SNc) is responsible for the principal motor symptoms of Parkinson’s disease (PD) The etiopathology of their death remains unknown many, varied and often interacting mechanisms have been proposed, including mitochondrial dysfunction, protein mishandling, inflammation, oxidative stress, genetic and environmental factors, and normal ageing (Chan et al, 2007; Sulzer, 2007; Schapira, 2008; Gasser, 2010; Guzman et al, 2010; Martin et al, 2010; Obeso et al, 2010; Surmeier et al, 2010a,b). The tight energy budget that these morphological features impose on SNc dopamine neurons is likely to be a critical factor in their susceptibility in PD and animal models of PD in that they are under a bio-energetic demand
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