Presence of proNGF-Sortilin Signaling Complex in Nigral Dopamine Neurons and Its Variation in Relation to Aging, Lactacystin and 6-OHDA Insults

Yi Xia,Xiao-Long Sun,Jing-Jie Wang,Bei-Yu Chen,Ken Yung,Guo-Dong Gao,Liang-Wei Chen,Li Duan

doi:10.3390/ijms140714085

Yi Xia, Xiao-Long Sun + Show 6 more

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https://doi.org/10.3390/ijms140714085

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Abstract

Growing evidence has shown that proNGF-p75NTR-sortilin signaling might be a crucial factor in neurodegeneration, but it remains unclear if it may function in nigral neurons under aging and disease. The purpose of this study is to examine and quantify proNGF and sortilin expression in the substantia nigra and dynamic changes of aging in lactacystin and 6-hydroxydopamine (6-OHDA) rat models of Parkinson’s disease using immunofluorescence, electronic microscopy, western blot and FLIVO staining methods. The expression of proNGF and sortilin was abundantly and selectively identified in tyrosine hydroxylase (TH)-containing dopamine neurons in the substantia nigra. These proNGF/TH, sortilin/TH-positive neurons were densely distributed in the ventral tier, while they were less distributed in the dorsal tier, where calbindin-D28K-containing neurons were numerously located. A correlated decrease of proNGF, sortilin and TH was also detected during animal aging process. While increase of proNGF, sortilin and cleaved (active) caspase-3 expression was found in the lactacystin model, dynamic proNGF and sortilin changes along with dopamine neuronal loss were demonstrated in the substantia nigra of both the lactacystin and 6-OHDA models. This study has thus revealed the presence of the proNGF-sortilin signaling complex in nigral dopamine neurons and its response to aging, lactacystin and 6-OHDA insults, suggesting that it might contribute to neuronal apoptosis or neurodegeneration during pathogenesis and disease progression of Parkinson’s disease; the underlying mechanism and key signaling pathways involved warrant further investigation.

Highlights

The proNGF/tyrosine hydroxylase (TH)-positive neurons were densely distributed in the ventral tier of the substantia nigra pars compacta (SNc), while they were scarce in the substantia nigra pars lateralis (SNr) and ventral tegemental area (VTA) (Figure 1A–C)
In a 6-OHDA rat model of this study, we found that proNGF-positive dopamine neurons were sensitive and highly susceptible to death after 6-OHDA insult in the substantia nigra
This study revealed the presence of the proNGF-sortilin signaling complex in the A9 ventral tier dopamine neuron group of substantia nigra, which appeared to be dynamic in expression levels and involved in nigral dopamine neuronal loss in aging, 6-OHDA and lactacystin rat models

Summary

Introduction

Parkinson’s disease (PD) is a severe debilitating and neurodegenerative disease in human beings that is characterized by motor symptoms of tremor, bradykinesia, rigidity and postural instability Since it results from the progressive death of dopamine neurons in the substantia nigra and pharmacological levodopa intervention to elevate dopamine alleviates the patient symptoms but cannot halt disease progression, neurotrophic therapy is widely recommended for PD treatment [1,2,3]. Dopamine neurons, those located in the ventral tier group of substantia nigra pars compacta with their dendrite extension ventrally into the substantia nigra pars reticularis (and biochemically calbindin-D28K negative), showed selective neuronal cell death or high susceptibility to various neurotoxin insults, e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), or lactacystin that were used to induce PD animal models [4,5,6]. Abnormality in neurotrophic support or deficiency in neurotrophic factor might be significant contributing factors in neurodegeneration, pathogenesis and progression of PD [2,7]

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