Lesch-Nyhan Syndrome and Dopaminergic Activity in the Basal Ganglia

This is a great article on the fairly selective involvement of the basal ganglia in Lesch-Nyhan syndrome, which is a genetic disorder that reduces the activity of hypoxanthine-guanine phosphoribosyltransferase (abbreviated HGPRT or HPRT, etc.) to 1.5-10 percent of the activity in normal people and reduces dopamine levels, in the different subdivisions of the basal ganglia, by 67-82 percent:

http://www.ncbi.nlm.nih.gov/pubmed/10760551

That article cites references saying that the HPRT activity, overall, is not really higher in the basal ganglia, but the brain, in general, has a very high protein content of the HPRT enzyme (implying a generally high activity, across the brain as a whole), as noted in this article:

http://www.ncbi.nlm.nih.gov/pubmed/15711436

Those are both great articles, and the second one talks about the likelihood that astrocyte-derived purines are used heavily by neurons. But to say that the protein content of HPRT is not higher in the basal ganglia, in comparison to other parts of the brain, is not to say that some factor influencing the activity of HPRT (as the authors discuss in the context of PRPP, in the second article) is not selectively altered in the basal ganglia. I wonder if part of it is a higher metabolic requirement of the neurons, and maybe astrocytes, in the basal ganglia. It's hard to find articles that address questions like that. It might not be a greater mitochondrial density but a higher degree of dependence on glycolysis in addition to oxidative phosphorylation.

Lesch-Nyhan syndrome is really complex and mysterious, from a mechanistic standpoint. It's known that it drastically deranges dopaminergic transmission, and that first article talks about the way adenine nucleotide depletion, even more than the presence of excessive levels of xanthine or hypoxanthine or the depletion of guanine nucleotides, may actually be more of an important mechanism. I know the authors of one paper were suggesting that AICAR accumulation could be part of it:

http://www.ncbi.nlm.nih.gov/pubmed/15193365

One of the ideas of those authors is just that de novo purine biosynthesis becomes accelerated in some cells, in response to purine depletion, and leads to AICAR accumulation (which then disrupts metabolism or acts on adenosine receptors, as they proposed). It's obviously really complicated in Lesch-Nyhan syndrome, but it's reasonable to suspect some contribution of AICAR to dopaminergic dysfunction in general.

This selective involvement of the basal ganglia in Lesch-Nyhan syndrome is really relevant to understanding the potential of things like reduced folates and purines or even pyrimidines (given that pyrimidine metabolism can be deranged in Lesch-Nyhan syndrome also) in treating neurodegenerative and psychiatric disorders. I'll try to collect links to some of the many good articles on the neurotrophic and neuroprotective effects of purines.

Obviously there's only so much to be gained from just delivering exogenous purines or pyrimidines into the brain, but I think it's worth exploring some of these mechanisms. It's a really interesting area, and the nucleus accumbens and the ventral striatum, as a whole, are strongly affected, in terms of dopamine depletion and deranged dopaminergic activity, in Lesch-Nyhan syndrome. Changes in dopaminergic activity in those parts of the brain play significant roles in some psychiatric disorders and also in cognition. People with Lesch-Nyhan syndrome can have severe cognitive dysfunction, as discussed in the first article I linked to in this posting, and it's thought, as discussed in the article, that it's the circuit involving the dorsolateral prefrontal cortex and caudate nuclei that explain these cognitive deficits. Those pathways are required for "working memory" (http://www.jneurosci.org/cgi/content/full/17/10/3870). The precise details of neuroanatomy are not my strong suit, and I'm sorry that's vague. Suffice it to say, in general, that disturbances in the activities of dopaminergic neurons in the basal ganglia can have a major impact on cognitive functioning.