Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

The death of SNpc DAergic neurons
INTRODUCTION
The main pathological biochemical hallmark of PD is the death of DAergic
neurons residing in the ventral midbrain nucleus, called the SNpc. The cell bodies of the
SNpc neurons project primarily to the putamen and upward to the caudate nucleus
composing the nigrostriatal pathway. The loss of these neurons which contain
considerable amounts of neuromelanin leads to the neuropathological finding of SNpc
depigmentation (Figure 9; Marsden 1983). Consequently the death of nigrostriatal
DAergic neurones results in a loss of the neurotransmitter DA in the striatum, more
precisely in the dorsolateral putamen where the depletion of DA is most pronounced
(Bernheimer et al. 1973). This leads to the main motor features of PD as the striatum
integrates signals from the motor cortex and regulates neural circuits within the BG to
control movement. Furthermore this agrees well with the correlation between the pattern
of SNpc cell loss and the expression levels of the DA transporter (DAT) mRNA (Figure
10; Uhl et al. 1994).
Figure 9: SNpc depigmentation, appearance of normal (left) and Parkinsonian (right) human midbrain
(National Center for Biotechnology Information www.ncbi.nlm.nih.org)
At the onset of symptoms, approximately 60% of the SNpc DAergic neurones
and 80% of DA content in putamen have already been lost (Fearnley and Lees 1991,
Deumens et al. 2002). This suggests that neuronal death in PD may result from a “dying
back” process as the striatal DAergic nerve terminals seem to be the primary target of
neurodegeneration before subsequent cell body effects (Dauer and Przedborski 2003).
DA depletion causes a cascade of functional changes in BG circuitry as it leads to
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