Aging-US: Protein processing impairment in Parkinson’s disease09-21-2021
Aging-US published "Proteomic characterization of secretory granules in dopaminergic neurons indicates chromogranin/secretogranin-mediated protein processing impairment in Parkinson’s disease" which reported that the number of SGs in tyrosine hydroxylase-positive neurons and the marker proteins secretogranin III significantly decreased in the substantia nigra and striatum regions of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine exposed mice.
Proteomic study of SGs purified from the dopaminergic SH-sy5Y cells under 1-methyl-4-phenylpyridinium treatments identified 536 significantly differentially expressed proteins. Protein-protein interaction analysis of 56 secretory proteins and 140 secreted proteins suggested that the peptide processing mediated by chromogranin/secretogranin in SGs was remarkably compromised, accompanied by decreased candidate proteins and peptides neurosecretory protein, neuropeptide Y, apolipoprotein E, and an increased level of proenkephalin.
The classical pathological characteristics of PD are progressive injury and loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites. The molecular mechanisms underlying PD are yet poorly understood due to a large number of factors involved and their complicated interplay. Merging studies implicate dysfunction of vesicle transport as an underlying mechanism of PD.
SGs represent the primary subcellular site for the biosynthesis, storage, and release of neuropeptides and hormones. They are filled with cargo at the trans-Golgi network to form primary vesicles, undergo maturation step as they travel along cytoskeletal filaments, and finally release the processed proteins responding to calcium signals. SGs secretory and processing machinery require orchestrated actions of an incredible repertoire of lipids, ATP, cytoskeletal filaments, and enzymes.
Scg3 acts as a bridge between chromogranin A and the cargo aggregates. It also participates in early peptide processing by interacting with carboxypeptidase E in the vesicle membrane. In these authors previous studies, a toxin-induced by dopaminergic neuron model of PD was established with paraquat.
Figure 7. Enrichment and PPI analysis of 56 significantly differentially expressed secretory granule proteins and 140 secreted proteins. (A) The top 10 enriched KEGG pathways of the 56 secretory granules proteins and 140 secreted proteins. (B–C) Candidate proteins interacting with secretogranins in peptide processing in SGs indicated by the PPI network. (D) The expressions of some secretogranins-related candidate neuropeptides and neuroendocrine hormones are verified using real-time PCR. Two-tailed unpaired Student t-tests were performed between the control and treated groups. *Statistically significant with P < 0.05; Error bars are SD; N = 3.
The Zhan Research Team concluded in their Aging-US Research Output that three of the 56 significantly differentially expressed proteins in «secretory granules» have also been identified or predicted in other omics studies of PD. Calmodulin 3 encodes a family of proteins that bind calcium and function as an enzymatic co-factor. Moreover, CALM3 was predicted as one of the prioritizing genes for PD after co-analysis of DEGs from the above microarray with the established PD associated-genes using a network science approach.
Full Text - https://www.aging-us.com/article/203415/text
Correspondence to: Xiaoni Zhan email: firstname.lastname@example.org
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.