PROJECT SUMMARY / ABSTRACT
There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive
neurodevelopmental disorder (NDD) caused by mutations in the transcriptional regulator MECP2. Hence, the
overall goal of this proposal is to understand the underlying pathophysiology of RTT, and identify novel
therapeutic avenues for this devastating disorder. Mecp2 mutant mice (male null mice, and female heterozygous
mice) exhibit a range of neurological abnormalities that recapitulate the human disorder, including reduced
neuronal dendritic complexity and soma size, and severe motor deficits. Importantly, selectively re-expressing
Mecp2 in adult mice has shown that RTT symptoms can be partially reversed, suggesting that restoration of
homeostasis of downstream targets of MeCP2 could also reverse or alleviate RTT symptoms.
One such potential downstream therapeutic target is NF-¿B. My previous work demonstrated that a consequence
of Mecp2 loss of function is up-regulation of Irak1, leading to aberrant NF-¿B signaling (Kishi* and MacDonald*
et al, Nature Communications 2016). Strikingly, genetically reducing the NF-¿B pathway in Mecp2-null male mice
partially rescues their reduced cortical dendritic complexity and substantially extends their normally shortened
lifespan. Further, our preliminary data demonstrate that dietary supplementation with the NF-¿B inhibitor vitamin
D (VitD) partially rescues Mecp2-null phenotypes in male mice. Intriguingly, VitD deficiency is highly prevalent
in RTT patients, and has been implicated in multiple other NDDs, including autism spectrum disorders (ASD).
We thus hypothesize that attenuation of NF-¿B signaling, via dietary supplementation with VitD, could have
broad therapeutic benefit in RTT, and potentially other neurological disorders with overlapping pathology.
We propose to test our hypotheses by comparing the in vivo therapeutic potential of VitD supplementation and
genetic attenuation of NF-¿B in female Mecp2 heterozygous mice (Aim 1), determining whether vitamin D
supplementation rescues RTT cortical neuronal phenotypes via cell autonomous or cell-non-autonomous
mechanisms (Aim 2), and determining underlying molecular mechanisms of this phenotypic rescue (Aim 3). We
will take a unique, integrative approach, investigating phenotypic rescue from the molecular (transcriptome) and
cellular level, to the level of neuronal and dendritic connectivity, to behavior. Although VitD supplementation may
not provide a “cure” for RTT, any phenotypic improvement from such a simple, cost-effective supplement would
be extremely exciting, with the potential for quality of life improvements. Further, we will identify molecular
mechanisms underpinning the phenotypic improvements, which could lead to additional new therapeutic targets,
for RTT and other neurological disorders with overlapping pathology.
