| First Author | Larasati YA | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 40 | Pages | eabn9350 |
| PubMed ID | 36206333 | Mgi Jnum | J:360408 |
| Mgi Id | MGI:7379728 | Doi | 10.1126/sciadv.abn9350 |
| Citation | Larasati YA, et al. (2022) Restoration of the GTPase activity and cellular interactions of Galphao mutants by Zn(2+) in GNAO1 encephalopathy models. Sci Adv 8(40):eabn9350 |
| abstractText | De novo point mutations in GNAO1, gene encoding the major neuronal G protein Galphao, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly(203), Arg(209), or Glu(246); we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln(205) critical for GTP hydrolysis, resulting in constitutive GTP binding by Galphao. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners. Through high-throughput screening of approved drugs, we identify zinc pyrithione and Zn(2+) as agents restoring active conformation, GTPase activity, and cellular interactions of the encephalopathy mutants, with negligible effects on wild-type Galphao. We describe a Drosophila model of GNAO1 encephalopathy where dietary zinc restores the motor function and longevity of the mutant flies. Zinc supplements are approved for diverse human neurological conditions. Our work provides insights into the molecular etiology of GNAO1 encephalopathy and defines a potential therapy for the patients. |
