HD Lighthouse Contributing Editor's Comment: In the study below, researchers showed that HD brain cells are much more sensitive to dopamine than non-HD cells. Dopamine levels which cause no harm to non-HD cells initiate cell death in the medium spiny neurons of the striatum of those with Huntington's Disease. Dopamine also contributes to aggregate formation. Although aggregates in and of themselves are probably not a primary defect, they do indicate early disease pathology.

There are two ways that mutant huntingtin and dopamine cause cell dysfunction and death. One is through the stimulation of an apoptotic signaling pathrway (in other words activating programmed cell death). The mediating factor here appears to be reactive oxidative species (small molecules which cause oxidative damage) -- and that's the connection with impaired cellular metabolism which is now believed by Marcy MacDonald and others to be a primary defect in HD. Dopamine can autooxidize and form ROS and this is associated with aging which may explain why even though the HD gene is present from birth, the disease is not.

The other way is through the stimulation of dopamine 2 receptors. The cells were rescued by a combination of ascorbate, an ROS scavenger, and a dopamine 2 receptor antagonist. Both were needed in combination to treat the cells!

This study is interesting for several reasons. First, it once again shows the value of testing combinations of potential therapies. Second, it reinforces the importance of antioxidants such as Vitamin C. Third, it suggests that neuroleptics which block the D2 receptor or which deplete dopamine might have therapeutic effects. Neuroleptics which are D2 antagonists include quetiapine (Seroquel), olanzapine (Zyprexa), resperidone, clozapine, and sulpiride. Tetrabenazine is a dopamine depleter.

--Marsha L. Miller, Ph.D.
Posted to the HDL: 28 Sep 2005

Unraveling a role for dopamine in Huntington's disease: The dual role of reactive oxygen species and D2 receptor stimulation.

Charvin, D. , Vanhoutte, P., Pages, C., Borelli, E., Caboche, J.

Huntington's disease (HD), an inherited neurodegenerative disorder, results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation leads to protein aggregation and neurotoxicity. Despite its widespread expression in the brain and body, mutated huntingtin causes selective degeneration of striatal projection neurons. In the present study, we investigate the role of dopamine (DA) in this preferential vulnerability. Using primary cultures of striatal neurons transiently expressing GFP-tagged-exon 1 of mutated huntingtin, we show that low doses of DA (100 muM) act synergistically with mutated huntingtin to activate the proapoptotic transcription factor c-Jun. Surprisingly, DA also increases aggregate formation of mutated huntingtin in all cellular compartments, including neurites, soma, and nuclei. DA-dependent potentiation of c-Jun activation was reversed by ascorbate, a reactive oxygen species (ROS) scavenger, and SP-600125, a selective inhibitor of the c-Jun N-terminal kinase (JNK) pathway. By contrast, DA effects on aggregate formation were reversed by a selective D2 receptor antagonist and reproduced by a D2 agonist. Similarly, striatal neurons from D2 knockout mice showed no effect of DA on aggregate formation. Blocking ROS production, JNK activation, or D2 receptor stimulation significantly reversed DA aggravation of mutated huntingtin-induced striatal death. The combined treatment with the ROS scavenger and D2 antagonist totally reversed DA's effects on mutated huntingtin-induced striatal death. Thus, the present results provide insights into the cellular mechanisms that govern striatal vulnerability in HD and strongly support a dual role of JNK activation and D2 receptor signaling in this process.

Tracked on the Lighthouse:
dopamine

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Source: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12218-23. Epub 2005 Aug 15.

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