Funding Research for Treatments and a Cure

Shared cellular mechanisms in Angelman syndrome and Christianson syndrome
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Dr. Eric Morrow Dr. Eric Morrow Brown University

Shared cellular mechanisms in Angelman syndrome and Christianson syndrome

Approximately 90% of males diagnosed with Christianson syndrome (CS) meet research criteria for a clinical diagnosis of Angelman syndrome (AS). CS is caused by loss-of-function (LoF) mutations in the X-linked, endosomal Na+/H+ exchanger 6 (NHE6) and was originally termed “X-linked Angelman syndrome”. The shared clinical spectra between CS and AS suggest that the E3 ubiquitin ligase UBE3A, which is mutated or deficient in AS, may function in a convergent cellular pathway with NHE6.

Preliminary data support both a biochemical interaction between UBE3A and NHE6, as well as a functional relationship between these proteins. NHE6 functions as a proton leak from organelles and LoF mutations in NHE6 lead to over-acidification of endosomes. UBE3A is involved in protein trafficking and degradation. Also, lack of UBE3A has been found to lead to alkalinization of the Golgi complex. Our central hypothesis is that UBE3A controls trafficking and degradation of NHEs, and that perturbations in UBE3A activity (through LoF mutations) cause abnormalities in the regulation of intra-organellar pH as a result of mislocalization and aberrant accumulation of NHEs. Such abnormalities in intra-organellar pH will disturb organellar functions, including protein processing, trafficking, and signaling, and ultimately disrupt circuit development. Using biochemical and morphological methods, we will:  (1) determine the extent to which UBE3A governs the trafficking and degradation of NHE proteins; and (2) investigate perturbations in regulation of intra-organellar pH mediated by UBE3A and NHE6.

Discovery of a shared pathway for UBE3A and NHEs involving intra-organellar pH would be fortuitous because drugs, including FDA-approved agents, known to target this cellular process are currently available. Therefore, success in this research would lay the foundation for future drug screening in available models of disease, including both patient-derived induced pluripotent stem cells (iPSCs) and animal models. The proposed studies are innovative in that they include live-cell imaging of intra-organellar pH in neurons, from mouse and from patient-derived iPSCs, by targeting ratiometric pHluorin to specific organellar compartments. The research is significant to AS because: (1) the discovery of functional linkages between genes associated with AS and other neurogenetic disorders develops more unified pathogenic mechanisms and broadens pathophysiological mechanisms and treatment targets; and more specifically, (2) a role for UBE3A in regulation of intra-organellar pH will yield a new druggable pathway for therapeutics in AS.