This paper documents activation of an unfolded protein response (UPR) in oligodendrocytes in mouse models and a human patient with Pelizaeus-Mezbacher Disease (PMD) and goes on to show that mice lacking the Chop gene have a much more severe course of what is otherwise a mild disease associated with the rumpshaker (rsh) allele of Plp1 . This last observation is the highlight of the paper as it implicates CHOP , a gene that functions in the UPR, in modulating the severity of PMD and implies that ER stress and the UPR are central to the pathogenesis of PMD. It also represents the first example in which CHOP protects against cell death during ER stress, a point that is discussed in detail in the paper.

Unfortunately the data supporting the central conclusion of this paper are weakened by a methodological limitation that may not have received sufficient emphasis. The Chop -/- ; Plp1 rsh mice that exhibited the high mortality were matched against Chop -/- ; Plp1 WT siblings and not against contemporaneous sibling with Chop +/- ; Plp1 rsh and Chop +/+ ; Plp1 rsh genotypes; in other words the impact of Chop-/- on the phenotype of Plp1 rsh was compared in strain-discordant historical controls. It is possible therefore that the differences in outcome attributed to the Chop genotype reflect strain differences in mice or some inter-current perturbation (e.g. viral infection) that happened to manifest itself at the time when the Chop -/- ; Plp1 rsh colony was being followed, but would have impacted on the health of Plp1 rsh male of any Chop genotype had they been exposed to it. These concerns are not merely generic, as Ian Griffith and Klaus-Armin Nave's lab have found that in their labs the phenotype of Plp1 rsh is highly strain dependent (Al-Saktawi et al. Genetic background determines the phenotypic severity of the Plp rumpshaker mutation. 2002 J. Neurosci. Res. in press).

It may also be worth mentioning that the study published in Neuron was conceived as a collaboration between my lab and Alex Gow's lab in 1998. We contributed mutant mice, antibodies and advice and reviewed the data and experimental strategies periodically with Alex. However, when it came time to publish the results, in February 2002 we expressed our concerns about the crucial mouse experiment and insisted that it be repeated with contemporaneous sibling controls. Alex refused and therefore I declined to co-author this paper.

David Ron
NYU School of Medicine
December 2, 2002