First author Heliane Serra and colleagues at the University of Minnesota, Minneapolis, made the neurodevelopmental connection by doing what all good scientists do best: following up on an interesting though puzzling observation. Back in 1995, Orr and colleagues noticed that one particular strain of ataxin 1 transgenic mouse—the BO4 strain—developed very severe ataxia even though it expressed relatively low amounts of mutant ataxin. Because the BO4 animals begin expression of the transgene (SCA1[82Q]) at postnatal day 2, rather than 8 to 12 days later as in most other strains, the researchers posited that a developmental disruption was responsible for the severity of the damage to BO4 mice. Now, using doxycycline-regulated expression of the transgene, Serra and colleagues have been able to put that theory to the test.

Knowing that the first 3 weeks after birth are critical for Purkinje and cerebellar development in mice, Serra used the doxycycline-regulated promoter to turn on expression of mutant ataxin 1 for 12 weeks starting either at postnatal week 2 or much later in development at postnatal week 14. When the researchers examined the animals after the 12 weeks of active gene expression, they found that the delay in expression almost completely protected the animals from the toxic effects of the polyglutamine-expanded ataxin. Mice that developed normally for 14 weeks performed much better in the rotarod compared to animals that expressed the mutant protein at postnatal week 2, and their Purkinje and cerebellar cell morphology was almost indistinguishable from that in wild-type animals. In contrast, the mice that began expressing mutant ataxin 1 earlier had moderate disease symptoms, as seen previously, and readily apparent dendritic atrophy in Purkinje cell layers. Even when the researchers allowed expression of the mutant gene to continue for 24 weeks, it had little additional effect on the animals if expression started post-development.

The researchers combined two other observations to get a handle on how mutant ataxin 1 affects development. They had previously generated microarray expression profiles for both SCA1 and the retinoid-related orphan transcription factor, RORα. The latter is deleted in staggerer mice, which have aberrant Purkinje cell maturation. Comparing both, Serra and colleagues found that the data sets had considerable overlap—most conspicuously, all four genes to which RORα is supposed to bind are downregulated by mutant ataxin 1. Serra subsequently found that levels of RORα are reduced in Purkinje cells expressing mutant ataxin 1, and that loss of RORα enhances mutant ataxin 1 pathology. They used immunoprecipitation experiments to demonstrate that the two proteins interact, though not directly. The interaction is most likely through Tip60, a coactivator that is of considerable interest to AD researchers because it has been found in a troika with Fe65 and the APP intracellular domain (see ARF related news story).

“One key implication of the Serra et al. (2006) study is that adult neurons can ‘remember’ untoward events that occur during key developmental windows,” writes Albert La Spada, University of Washington, Seattle, in an accompanying Cell Preview. He also writes that “it is very intriguing that the window is so narrow,”—the data suggest that the presence of mutant protein for as little as 5 days is sufficient to establish the conditions for subsequent neurotoxicity. It will be interesting to see if any other neurodegenerative diseases are governed by similar neurodevelopmental windows.—Tom Fagan.

Reference:
Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. November 17, 2006;127:697-708. Abstract

La Spada AR. Neurodegeneration: A case of arrested development? Cell November 17, 2006;127:669-671. Abstract