The Regulated Secretory Pathway and Human Disease: Insights from Gene Variants and Single Nucleotide Polymorphisms

Abstract

The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

Hippocampal Pruning as a New Theory of Schizophrenia Etiopathogenesis

“…This is also consistent with the neurodevelopmental theory foundation that SKZ is a consequence of global alterations in brain connectivity and transmission regulation [93,94]. Intriguingly, various secreted and secretion-related proteins already showed significant role in shaping SKZ risk [95][96][97]. As secreted proteins appear to be the evolutionarily newest, we can suppose that evolution through mammals, to adapt this biological process at the higher complexity of brain, worked more on a fine orchestration and harmonization of its parts with the increasing number of simultaneous nervous process carried out, rather than modifications in the dendritic cut realization itself.…”

60 YEARS OF POMC: Biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides

“…As already stated, the final peptides produced in the hypothalamus are similar to those from the IL; α-MSH and β-endorphin. These neurons are responsive to leptin and insulin, and other neural and humeral signals, as indicators of peripheral energy stores in vivo , and are primarily known to centrally regulate food intake through α-MSH action on the melanocortin 4 receptors (MC4R) in other hypothalamic areas and in areas of the brainstem important in regulating energy balance (Cowley, et al 2001; Lin and Salton 2013). Mutations in MC4R were first reported to be associated with inherited human obesity in 2008 (Loos, et al 2008) demonstrating the importance of this signaling pathway in human health.…”

Mechanisms and regulation of neurotrophin synthesis and secretion

“…Compared to other neurotrophins, BDNF is targeted to the regulated secretory vesicles most efficiently 9,20. Many explanations have been documented for this efficient targeting to the regulated pathway of secretion.…”