Archive for the ‘NURR1’ Category

Nuclear receptor related 1 protein
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Yesterday, there were some grumblings on the nomination of Francis Collins to the head of NIH.  Some folks feel that the genome-wide, genome-everything approach to medicine has somewhat over-promised and under-delivered in its promise to elucidate the molecular pathways of human disease.  In the field of mental health, the whole-genome era is just now dawning and ever more, ever larger studies are reporting the results of GWAS and other global sweeps for genetic risk.  So, its fair to ask whether the whole-genome approach hath bourne the promised fruit.  Exactly, how much of the overall risk of illness can we account for using the present genetic knowledge? I’d like to know & will be working to track this “bottom line” statistic in the future.

However, I suspect that the numbers may be humbling.  In part, because of the tricky ways in which the genome interacts with the pre- & post-natal environment during development.  For example, consider the recent paper by Saijo et al. “A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death” [doi 10.1016/j.cell.2009.01.038].  Here the team considers neurodegenerative processes and how the tissues of the brain cope with unwanted oxidative pro-inflammatory damage.  Specifically, the team shows that Nurr1, a so-called orphan nuclear receptor that is known to regulate the development of midbrain dopamine neurons, actually has another function – one that occurs inside the microglia of the brain (special macrophage-like cells of the brain that can clear infection – ideally without harming surrounding neural circuitry).  The team injected (into the midbrain) an evil, bacteria-like, oxidative sludge known as lipopolysaccharide (LPS) which triggers a full-blown immunologic alarm that often has the unwanted side-effect of inducing the death of dopaminergic neurons.  This is very BAD – as it creates a Parkinsonian condition – but, nevertheless is something that our bodies and brain must cope with throughout our life-cycle since we’re always being exposed to bacteria and other pathogens.  The team finds that the cytotoxic response of microglia is repressed by Nurr1 such that when Nurr1 expression is blocked,  the microglia are more active and then, unfortunately, cause more collateral damage to the dopaminergic cells in their efforts to clear the LPS.  So it seems that Nurr1 helps to save dopaminergic neurons by dampening down the normal inflammation response systems that – when faced with foreign infections – can cause collateral damage in their efforts to clear the infection.  Wow, so Nurr1 helps to give birth to dopamine neurons and to keep them safe from harm. Such a gene, is one I’d hope would work well.  Not surprisingly, mutations in Nurr1 have been associated with the risk of Parkinson’s Disease.

More interestingly, the way in which Nurr1 seems to carry out its regulation of this very common type of gene-x-environment (infection) interaction is through a so-called CoREST repressor complex which is implicated in various epigenetic forms of gene regulation – which can have long-lasting effects on cells, perhaps long-after the infection has cleared.

Thus, just this one story around little, itty bitty DNA binding factor Nurr1, who, alone can’t account for more than a hair’s worth of genetic risk, may, in fact, play a critical role in the onset of complex mental illness.  It would seem perhaps that identifying genetic risk factors may only be the beginning of a long, complex search for the biological roots of mental disability – where genes and environment weave intractable tales.

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