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

Gehua Wen,Hao Pang,Enzhu Jiang,Xu Wu,Xique Zhang,Xiaoni Zhan

doi:10.18632/aging.203415

Gehua Wen, Hao Pang + Show 4 more

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https://doi.org/10.18632/aging.203415

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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.

Highlights

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder
To evaluate whether the MPTP-induced PD model was successfully established, the number of dopaminergic neurons in the substantia nigra (SN) and corpus striatum (CPU) were assessed by the immunohistochemistry of tyrosine hydroxylase (TH)
The results showed that MPTP lesion for 5 successive days significantly decreased TH-positive cell bodies in SN and TH-positive cell terminals in the CPU compared with the control group (62.2% and 71.17% of control, respectively), suggesting there were an injury and loss of dopaminergic neurons after MPTP exposure (Figure 1A– 1C)

Summary

Introduction

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The classical pathological characteristics of PD are progressive injury and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies and Lewy neurites [1, 2]. The molecular mechanisms underlying PD are yet poorly understood due to a large number of factors involved and their complicated interplay [3,4,5,6,7,8]. Merging studies implicate dysfunction of vesicle transport as an underlying mechanism of PD. The abnormal fusion and cycling of synaptic vesicles (SVs) are found at presynaptic terminals of the dopaminergic neuron [9, 10]. Without proper maintenance of SV trafficking, endocytosis, and macroautophagy, synapses become dysfunctional, leading to impaired secretion of dopamine and neurodegeneration [2, 9]

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