Trends in Neurosciences
ViewpointNeuronal cell death in Huntington’s disease: a potential role for dopamine
Section snippets
Models of HD: mitochondrial dysfunction and excitotoxicity
Early reports of reductions in mitochondrial complexes II and IV in the caudate of individuals with HD (9, 10) provided the first clues that defects in energy metabolism could be pathogenically relevant in HD. In support of this idea were the observations that damage to basal-ganglia structures occurred in humans who attempted suicide by ingestion of cyanide11 or by inhalation of carbon monoxide12 (both of which block complex IV of the mitochondrial respiratory chain). In the mid 1980s, it was
Oxidative stress and HD
Compounds such as superoxide and hydroxyl radicals, are endogenously formed, highly reactive molecules that can oxidize lipids, proteins and DNA, thereby altering neuronal structure and function37. Several findings suggest that reactive oxygen species (ROS) might be important mediators of cell death in HD. For example, levels of the markers of oxidative stress, which include oxidized glutathione38 and the nucleotide 8-hydroxydeoxyguanosine25, are significantly increased in the striatum in
Dopamine as a neurotoxin
The neostriatum is innervated densely by dopaminergic fibers that originate in the substantia nigra. Despite the high concentrations of dopamine (DA) that exist in the striatum54, there is increasing evidence that DA, or one of its metabolites, might be neurotoxic. Intraparenchymal injections of DA result in dose-dependent striatal damage, consisting of neuronal loss, terminal degeneration and gliosis55, 56. Dopamine is also toxic in dissociated rat mesencephalic57, striatal58, 59 and cerebral
Dopamine and oxidative stress
There are compelling data that DA or its metabolites, or both, can generate ROS. In rodents, DA is metabolized via monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAC) and hydrogen peroxide (H2O2) (Ref. 64). Although not lethal, H2O2 can react with transition metals, such as iron, and generate highly toxic hydroxyl radicals via ‘Fenton-type’ chemistry37. Dopamine can also undergo nonenzymatic autoxidation with molecular O2 to form radical semiubiquinones and superoxide radicals65.
Dopamine-mediated toxicity and EAA function
Dopamine-mediated toxicity might also involve EAA function. This was deduced initially from studies in which DA levels were increased in the striatum after hypoxic insult71, and later when it was demonstrated that dopamine denervation attenuated hypoxic–ischemic brain damage72 (a process mediated, in part, by activation of EAA receptors) and EAA-induced striatal lesions55, 73, 74. Elevated levels of DA can inhibit glutamate uptake75, perhaps via the action of DA-derived ROS (Ref. 76). This
Dopamine-mediated toxicity is enhanced in ‘sick’ neurons
Although tolerated under normal physiological conditions, it is conceivable that endogenous levels of DA might potentiate cell death in neurons with bioenergetic defects. Recently, it has been demonstrated that depletion of striatal DA, with the neurotoxin 6-hydroxydopamine (6-OHDA), was neuroprotective against tissue damage induced by intraparenchymal malonate injections93 and systemic administration of 3-NP (93, 94). The acute administration of methamphetamine (which causes the massive
Relevance to HD
There is considerable circumstantial evidence that aberrant DA metabolism might occur in HD. This idea was first proposed when over a third of asymptomatic relatives (10 out of 28) of individuals with HD developed dyskinesias after being given l-DOPA (Ref. 101). Later it was reported that DA-receptor antagonists and release inhibitors were effective in treating the chorea associated with HD and that several (but not all) dopamine-receptor agonists exacerbated these movements102. Interestingly,
Concluding remarks
On the basis of the data presented herein, we hypothesize that DA, which has long been linked to dopaminergic cell loss in Parkinson’s disease, contributes to striatal cell death in HD (Fig. 1). In this regard, it is interesting to note that catecholamines can also enhance β-amyloid neurotoxicity122, which stresses the potential importance of this class of neurotransmitter in other neurodegenerative disorders of aging. An important question that remains unanswered is how mutant huntingtin
Acknowledgements
The authors’ research was supported by NIH grant NS01941 to W.F.M. The authors thank Don M. Gash, Avi Nath, Joe Springer and Daret St Clair for their helpful comments.
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