Elsevier

The Lancet Neurology

Volume 6, Issue 10, October 2007, Pages 933-938
The Lancet Neurology

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Calcium, ageing, and neuronal vulnerability in Parkinson's disease

https://doi.org/10.1016/S1474-4422(07)70246-6Get rights and content

Summary

Parkinson's disease is a common neurodegenerative disorder of unknown cause. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of Parkinson's disease are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is their increasing reliance on Ca2+ channels to maintain autonomous activity with age. This reliance could pose a sustained metabolic stress on mitochondria, accelerating cellular ageing and death. The Ca2+ channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca2+-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades. These studies also suggest that, although genetic and environmental factors can hasten its onset, Parkinson's disease stems from a distinctive neuronal design common to all human beings, making its appearance simply a matter of time.

Introduction

Parkinson's disease is a common neurodegenerative disease strongly associated with ageing.1 The cardinal motor symptoms of Parkinson's disease are bradykinesia, rigidity, and tremor.1, 2 Parkinson's disease has no cure and nothing is known to slow its progression.3, 4 Several regions of the brain display signs of pathology in Parkinson's disease,5 but the motor symptoms of the disease are clearly linked with the degeneration and death of dopamine neurons in the substantia nigra pars compacta (SNc).6, 7 The clinical efficacy of levodopa—a dopamine precursor—is testament to the centrality of these neurons in Parkinson's disease.

Why dopamine neurons are preferentially lost in Parkinson's disease is not clear. Perhaps the most widely held theory suggests that the cause is dopamine itself. There is evidence that oxidation of cytosolic dopamine (and its metabolites) leads to the production of damaging free radicals.8 However, there are many reasons to doubt that this type of cellular stress has a key role in normal ageing and Parkinson's disease. For example, there is considerable regional variability in the vulnerability of dopamine neurons in Parkinson's disease, with some classes showing no signs of loss at all.9, 10, 11, 12, 13 Moreover, administration of levodopa (which increases dopamine levels) in patients with Parkinson's disease does not accelerate disease progression,14 suggesting that, at normal cytosolic concentrations, dopamine is not a substantial source of reactive oxidative products and stress.

If not dopamine, then what? Several lines of study suggest that mitochondrial and proteasome dysfunction are involved in Parkinson's disease.15, 16, 17 However, why SNc dopamine neurons should be any more vulnerable to this type of dysfunction than other neurons is not clear. Similarly, genetic studies have identified several potential determinants of Parkinson's disease but have not provided many clues as to selective vulnerability, at least not to this point. None of the genes linked to familial forms of Parkinson's disease are preferentially expressed by SNc dopamine neurons, suggesting that these neurons display some epigenetic feature that increases the cellular effect of polymorphisms or mutations.

Section snippets

SNc dopamine neurons and calcium

The physiology of SNc dopamine neurons might hold the key needed to unlock this mystery. Unlike most neurons in the brain, SNc dopamine neurons are autonomously active; that is, they generate action potentials at a clock-like 2–4 Hz in the absence of synaptic input. In this respect, they are much like cardiac pacemakers. Although they display considerably more complex activity patterns in vivo than do cardiac cells,18 the foundation on which the activity is built is the same. Even more unusual

Calcium, ageing, and Parkinson's disease

Although the demand on oxidative phosphorylation posed by the reliance on Ca2+ channels for pacemaking is not lethal, it might accelerate the ageing of SNc dopamine neurons. One of the oldest and most popular theories of ageing is that it is a direct consequence of accumulated mitochondrial DNA (mtDNA) damage produced by reactive oxygen species and related free radicals generated in the course of oxidative phosphorylation.32, 33 A corollary of this hypothesis is that the rate of ageing is

Staving off Parkinson's disease

If Parkinson's disease is a consequence of the accelerated ageing of neurons that rely heavily on Ca2+ channels (figure 2), then reducing this dependence should delay the onset of the disease and slow its progression. This might be possible with orally deliverable drugs shown to be safe in human beings.24 In mice, the reliance of SNc dopamine neurons on Ca2+ channels to drive pacemaking is developmentally regulated. Young neurons are autonomously active but generate this activity with channels

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