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Review
. 2014 Dec 15:8:152.
doi: 10.3389/fnana.2014.00152. eCollection 2014.

Molecular determinants of selective dopaminergic vulnerability in Parkinson's disease: an update

Lars Brichta  1 , Paul Greengard  1
Affiliations
Review

Molecular determinants of selective dopaminergic vulnerability in Parkinson's disease: an update

Lars Brichta et al. Front Neuroanat. .

Abstract

Numerous disorders of the central nervous system (CNS) are attributed to the selective death of distinct neuronal cell populations. Interestingly, in many of these conditions, a specific subset of neurons is extremely prone to degeneration while other, very similar neurons are less affected or even spared for many years. In Parkinson's disease (PD), the motor manifestations are primarily linked to the selective, progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). In contrast, the very similar DA neurons in the ventral tegmental area (VTA) demonstrate a much lower degree of degeneration. Elucidating the molecular mechanisms underlying the phenomenon of differential DA vulnerability in PD has proven extremely challenging. Moreover, an increasing number of studies demonstrate that considerable molecular and electrophysiologic heterogeneity exists among the DA neurons within the SNpc as well as those within the VTA, adding yet another layer of complexity to the selective DA vulnerability observed in PD. The discovery of key pathways that regulate this differential susceptibility of DA neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. This review provides an update on the molecular basis of the differential vulnerability of midbrain DA neurons in PD and highlights the most recent developments in this field.

Keywords: Parkinson’s disease; differential vulnerability; dopamine; selective vulnerability; substantia nigra; ventral tegmental area.

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Figures

Figure 1
Figure 1
Number of SNpc and VTA DA neurons in humans, monkeys, rats and mice. In adult C57BL/6 mice, approximately 8,000–12,000 TH-positive neurons are located in each of the two neuron groups bilaterally (German et al., ; Nelson et al., ; Jackson-Lewis and Przedborski, 2007). Studies in rats revealed about 21,000–25,000 TH-positive neurons in the SNpc and about 20,000–40,000 TH-positive neurons in the VTA bilaterally (German and Manaye, ; Nair-Roberts et al., 2008). In monkeys and humans, much higher numbers of DA neurons are found in the midbrain. Stereology studies counted approximately 120,000–270,000 TH-positive neurons bilaterally in the SNpc and about 110,000 TH-positive neurons bilaterally in the VTA in rhesus and squirrel monkeys (Emborg et al., ; McCormack et al., ; Collier et al., ; Kanaan et al., 2007). In humans, about 200,000–420,000 TH-positive neurons bilaterally were reported for the SNpc in adults and about 60,000–65,000 TH-positive neurons for the VTA (Hirsch et al., ; McRitchie et al., ; Damier et al., ; Chu et al., 2002).
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