This seems like an odd question given that only a small percentage of people actually get Parkinson’s disease. Nevertheless, the question has always perplexed me.

Here’s my rationale. The main neurons responsible for the motor
symptoms of Parkinson’s disease are dopamine-containing cells that project from the substantia nigra pars compacta to the striatum. In the striatum, each nigrostriatal dopamine neuron branches into a dizzying array of tiny appendages that make hundreds of thousands of synapses.^{1, 2} And these neurons do not merely send the occasional message. They are pacemakers, constantly firing at a slow, steady rate, hour after hour, year after year. Can you imagine how much energy it takes to constantly transport cargo to hundreds of thousands of branches? How many mitochondria these cells need to produce adequate energy? Recycle vesicles? Make new neurotransmitter? Get rid of old proteins and organelles? You’d think the nigrostriatal dopamine neurons would simply wear out in all of our brains.

Years ago when I was in graduate school, we talked about the nigrostriatal dopamine neurons as if they were the only neurons that died in Parkinson’s disease.  The focus was on motor symptoms such as tremor, bradykinesia, and difficulty initiating movement, which are thought to be caused by the death of nigrostriatal dopamine neurons. Today we know that Parkinson’s disease is associated with a host of nonmotor symptoms that are caused by the death of many other neuronal groups, many of which don’t even contain dopamine.

Researchers have identified a few interesting things about the various neuronal groups that die in Parkinson’s disease, features that distinguish them from neurons that remain healthy. First, they are projection neurons, as opposed to local circuit neurons, with axons that are disproportionately long and thin relative to their cell bodies.³ Second, their axons are unmyelinated or poorly myelinated.³ Many are pacemaker neurons, like the nigrostriatal dopamine neurons, that possess a specific L-type calcium channel.⁴ As described earlier, the nigrostriatal dopamine cells have tremendous terminal arborizations. The upshot of all these features is that they cost the neurons a great deal of energy. In other words, the vulnerable neurons must work hard all of the time. This overload may enhance their vulnerability to neurotoxins, metabolic challenges, infectious agents, or other insults,^{3, 5} causing them to die while their more relaxed neighbors survive.

As yet, we don’t know the nature of the insults that initiate the typically slow, progressive neuronal death that characterizes Parkinson’s disease. But we do know that the pattern of cell loss is not random. Only certain cells are vulnerable and, of course, only certain people. Why do one person’s busy cells survive and another person’s don’t? Are some people’s vulnerable cells undergoing apoptosis, or programmed cell death, at a higher rate, predisposing them to pathology?⁶ Are some people exposed to a toxin or pathogen that can’t be cleared by the overworked cells? How do these insults interact with genetic factors?

We don’t yet know the answers to these questions, but for my part, I’m grateful that these neurons keep plugging away as long as they do, and hope that one day soon we can plug them back in for people with Parkinson’s disease.

What do you think about the vulnerability of these highly active cells? I’d love to hear your thoughts–please comment!

References

1. Matsuda W, Furuta T, Nakamura KC, et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci. Jan 14 2009;29(2):444-453.
2. Arbuthnott GW, Wickens J. Space, time and dopamine. Trends Neurosci. Feb 2007;30(2):62-69.
3. Braak H, Rub U, Gai WP, Del Tredici K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna). May 2003;110(5):517-536.
4. Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT. Physiological phenotype and vulnerability in Parkinson’s disease. Cold Spring Harb Perspect Med. Jul 2012;2(7):a009290.
5. Parent M, Parent A. Relationship between axonal collateralization and neuronal degeneration in basal ganglia. J Neural Transm Suppl. 2006;70:4.
6. Jiang P, Gan M, Yen SH, Moussaud S, McLean PJ, Dickson DW. Proaggregant nuclear factor(s) trigger rapid formation of alpha-synuclein aggregates in apoptotic neurons. Acta Neuropathol. Feb 2 2016.