Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

Ghrelin as a Survival Hormone

“…Also of note, the increase in plasma ghrelin associated with both short-term and more chronic caloric restriction requires sympathetic activation of the highly-expressed β 1 -adrenergic receptors on ghrelin cells [32]. Other settings associated with high ghrelin include exposure to psychosocial stress [40] and Prader-Willi Syndrome, although in Prader-Willi Syndrome, it is unclear how much of this represents unprocessed ghrelin [13, 41]. The mechanisms that increase plasma ghrelin in those latter conditions are unclear.…”

Islet prohormone processing in health and disease

“…PC1/3 expression was recently reported to be reduced in Prader‐Willi syndrome—a syndrome of hyperphagic obesity associated with elevated PI levels. Genetic deletion of paternal SNORD116 in Prader‐Willi syndrome leads to diminished PC1/3 expression, likely via the transcription factor NHLH2 through an unknown mechanism. NHLH2 has been shown to positively regulate PCSK1 transcription through heterodimerization with STAT3 and PCSK1 promoter binding .…”

“…NHLH2 has been shown to positively regulate PCSK1 transcription through heterodimerization with STAT3 and PCSK1 promoter binding . Genetic deletion of paternal Snord116 in mice similarly leads to reduction of islet Pc1/3 and Pc2 expression, along with increased islet and circulating PI …”

“…12 Genetic deletion of paternal Snord116 in mice similarly leads to reduction of islet Pc1/3 and Pc2 expression, along with increased islet and circulating PI. 11 Mutations in the PCSK1 gene in humans were first discovered in a woman with hyperglycaemia during an oral glucose tolerance test (OGTT), with elevated 2 hours OGTT total and 65,66-split PI, 13 and extremely low circulating mature insulin. Combined with altered neuroendocrine secretion and processing defects, PCSK1 mutations were suspected, and the patient was confirmed to be compound heterozygous for PCSK1 null mutations.…”

Small molecule inhibitors of G9a reactivate the maternal PWS genes in Prader-Willi-Syndrome patient derived neural stem cells and differentiated neurons

“…Prohormone convertase PCSK1 deficiency has been identified as one a putative major contributor to the neuroendocrine phenotype of PWS. This result was further supported by the transcriptional profiling of hypothalami from the Snord116 p-/m+ mouse model (Bochukova et al, 2018; Burnett et al, 2017b; Wang et al, 2015; Zhang et al, 2012). In addition, SNORD116 has been indicated to play the most critical role in PWS etiology, which is corroborated with various genetic ablation studies using murine models (Bortolin-Cavaille and Cavaille, 2012; Burnett et al, 2017a; Ding et al, 2008; Gallagher et al, 2002; Polex-Wolf et al, 2018; Qi et al, 2016; Zhang et al, 2012).…”