Proteomic characterization of secretory granules in dopaminergic neurons indicates chromogranin/secretogranin-mediated protein processing impairment in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is an aging disorder related to vesicle transport dysfunctions and neurotransmitter secretion. Secretory granules (SGs) are large dense-core vesicles for the biosynthesis of neuropeptides and hormones. At present, the involvement of SGs impairment in PD remains unclear. In the current study, we found that the number of SGs in tyrosine hydroxylase-positive neurons and the marker proteins secretogranin III (Scg3) significantly decreased in the substantia nigra and striatum regions of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) exposed mice. Proteomic study of SGs purified from the dopaminergic SH-sy5Y cells under 1-methyl-4-phenylpyridinium (MPP+) treatments (ProteomeXchange PXD023937) identified 536 significantly differentially expressed proteins. The result indicated that disabled lysosome and peroxisome, lipid and energy metabolism disorders are three characteristic features. 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 (VGF), neuropeptide Y, apolipoprotein E, and an increased level of proenkephalin. The current study provided an extensive proteinogram of SGs in PD. It is helpful to understand the molecular mechanisms in the disease.

Characterizing neuroinflammation and identifying prenatal diagnostic markers for neural tube defects through integrated multi-omics analysis

“…Surprisingly, these genes have not been previously reported in relation to either human patients or animal models with NTDs. Among them, nervous system-related genes, including FABP7, CRMP1, and SCG3, play important roles in neural development, neurodegenerative disorders, and neuroendocrine systems [86][87][88][89][90]. On the other hand, immune system-related genes, including SLC16A10, RNASE1, and RNASE6, function in immune responses, antimicrobial activity, and enhancing anti-tumor immunity [91][92][93][94].…”

Tandem mass tag-based quantitative proteomic analysis of effects of multiple sevoflurane exposures on the cerebral cortex of neonatal and adult mice

“…CHGB is known to be associated with neurodegenerative diseases, including schizophrenia and Parkinson's disease ( 19 , 20 ). As a type of neuroendocrine secretory granule protein, CHGB plays a key role in the regulated secretory pathway, impacting the secretion of trophic factors that modulate synaptic maturation of developing neurons ( 21 ), and is involved in the regulation of synaptic plasticity, which is related to memory formation ( 22 ).…”

Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid spanning from healthy subjects to prodromal and manifest Parkinson’s disease

“…Secretogranin-2 regulates the packing and sorting of peptide hormones and neuropeptides into secretory vesicles and is generally considered a marker for secretory granules, dense-core vesicles in neurons and neuroendocrine cells 42 . Secretogranin-2 CSF levels were not only signi cantly lower in PD but also in iRBD compared with healthy controls, with the PD levels lying in between.…”