The previous blog post mentioned the idea that dopamine (DA) can regulate the extent of gap junction coupling between neurons. In Parkinson disease there is loss of dopamine-producing neurons (neurodegeneration) and one pharmacological approach to improving motor control is to give patients L-DOPA, the precursor for dopamine synthesis (see the figure). However, a common side effect of L-DOPA treatment is the eventual development of unwanted involuntary movements (dyskinesia).
Huntington disease is another neurodegenerative disease. Early symptoms seem to be due to loss of neurons in the striatum and include abnormal involuntary movements. An available pharmacological intervention for Huntington disease is tetrabenazine. Tetrabenazine inhibits the dopamine transporter (VMAT2) that transports dopamine into synaptic vesicles. In experimental animals, tetrabenazine reduces dopamine levels in the striatum.
It has been reported that Tetrabenazine is neuroprotective in Huntington’s disease mice. There is some evidence that dopamine contributes to neurodegeneration in the striatum (1). Most Huntington disease patients have an altered huntingtin protein due to a huntingtin gene that codes for an unusually long protein with a longer than normal polyglutamine domain. How the long form of the huntingtin protein causes loss of neurons is an active research topic. In Huntington disease there might be loss of a normal huntingtin function such as promotion of autophagy (2). The disease-causing huntingtin protein also seems to have additional functions not displayed by the normal version of the protein. It has been suggested that disease-causing huntingtin protein causes excess damage to DNA and inhibits DNA repair (3). It is possible that by inhibiting the transport of dopamine into synaptic vesicles, tetrabenazine is able to reduce dopamine-induced neurotoxicity in Huntington disease patients.
i) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease
ii) Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington’s disease
Image credits. The image is a diagram from a copyleft journal article. Interrelationships between dopamine metabolism, VMAT2, DAT, the generation of toxic species, oxidative stress and mitochondrial dysfunction in Parkinson’s disease Copyright Qi et al. distributed under the terms of the Creative Commons Attribution License.