Nurr1 (NR4A2) discovery

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Zetterström, Solomin, Jansson, Hoffer, Olson and Perlmann (Department of Neuroscience, Karolinska Institute, Stockholm), Science 1997. Le Weidong, Xu, Jankovic, Jiang, Appel, Smith and Vassilatis (Baylor College of Medicine, Houston), Nature Genetics 2003. Funders were not read.

What happened

• 1997. Nurr1 is a "switch" protein (an orphan nuclear receptor) turned on in developing dopamine neurons early. Mice lacking it failed to make midbrain dopamine neurons, were underactive (hypoactive) and died soon after birth. Nurr1 stayed switched on in adulthood. Mice with one working copy were otherwise apparently healthy but had less dopamine in the brain. The authors suggested that compounds that bind Nurr1 might treat Parkinson's.
• 2003. In 201 people with Parkinson's and 221 controls, two variants in the NR4A2 (Nurr1) gene (-291Tdel and -245T>G, both in the first exon) were found, each on one allele, in 10 of 107 familial cases and in none of 94 sporadic cases or 221 controls. The 10 carriers had a typical age at onset and features. The variants cut NR4A2 messenger RNA in cell lines and in the carriers' white blood cells, and affected transcription of the tyrosine hydroxylase gene (the dopamine-making enzyme).

Why it moved us toward a cure

It identified a master regulator of the cell type that dies in Parkinson's, and its link to dopamine production. It is the scientific root of the Nurr1 activator programme (landmark 149). The family finding hinted that too little Nurr1 may be a cause rather than only a bystander.

Outcome

Advanced. Nurr1 activators are now a drug programme: one, HL192, has passed a healthy-volunteer safety study, but none has been tested in people with Parkinson's. The 2003 family finding stays unconfirmed here (see below).

Sources

• Zetterström et al., Science 1997, DOI 10.1126/science.276.5310.248
• Le et al., Nat Genet 2003, DOI 10.1038/ng1066 (PMID 12496759)
• Not yet verified: whether other groups replicated the Le 2003 variants (a 2004 Neurology letter by Hering et al., "Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease", PMID 15079038, looks relevant but its result could not be read); funders of both papers. Authors, affiliations and results above are from the PubMed abstracts via Europe PMC.