MicroRNA expressing profiles in A53T mutant alpha-synuclein transgenic mice and Parkinsonian.

Mingshu Mo,Shuxuan Huang,Yousheng Xiao,Luan Cen,Xian Lin,Xinling Yang,Xiang Chen,Shaomin Li,Qin Luo,Limin Zhang,Pingyi Xu

doi:10.18632/oncotarget.13905

Abstract

α-synuclein gene mutations can cause α-synuclein protein aggregation in the midbrain of Parkinson's disease (PD) patients. MicroRNAs (miRNAs) play a key role in the metabolism of α-synuclein but the mechanism involved in synucleinopathy remains unclear. In this study, we investigated the miRNA profiles in A53T-α-synuclein transgenic mice and analyzed the candidate miRNAs in the cerebrospinal fluid (CSF) of PD patients. The 12-month A53T-transgenic mouse displayed hyperactive movement and anxiolytic-like behaviors with α-synuclein aggregation in midbrain. A total of 317,759 total and 289,207 unique small RNA sequences in the midbrain of mice were identified by high-throughput deep sequencing. We found 644 miRNAs were significantly changed in the transgenic mice. Based on the conserved characteristic of miRNAs, we selected 11 candidates from the 40 remarkably expressed miRNAs and explored their expression in 44 CSF samples collected from PD patients. The results revealed that 11 microRNAs were differently expressed in CSF, emphatically as miR-144-5p, miR-200a-3p and miR-542-3p, which were dramatically up-regulated in both A53T-transgenic mice and PD patients, and had a helpful accuracy for the PD prediction. The ordered logistic regression analysis showed that the severity of PD has strong correlation with an up-expression of miR-144-5p, miR-200a-3p and miR-542-3p in CSF. Taken together, our data suggested that miRNAs in CSF, such as miR-144-5p, miR-200a-3p and miR-542-3p, may be useful to the PD diagnosis as potential biomarkers.

Highlights

Parkinson’s disease (PD) is characterized by dopaminergic neuronal degeneration with α-synuclein (SNCA) deposition in midbrain [1]
In the miRNA signatures of PD, we found the miRNAs with dramatic change of expression, included miR-196a-5p, -196b-5p, -10b-3p, -10a-5p, -615-3p, -505-5p, -144-5p, -542-3p, -200a-3p, -182-5p and -451a that expressed in the body fluids and associated with mutant α-synuclein aggregation
As to the genotype factor, the homozygous offspring of alanine-53→threonine mutation (A53T) mice develop some paralysis-like symptoms and die approximately at 16-month old as reported by Jackson Laboratories, but the heterozygous offspring rarely show the similar pathology signs and the onset time will has 22-28 months delay [9, 42, 43]

Summary

Introduction

Parkinson’s disease (PD) is characterized by dopaminergic neuronal degeneration with α-synuclein (SNCA) deposition in midbrain [1]. The α-synuclein (α-syn) physiologically regulates dopamine (DA) transmission by modulating synaptic transport and tyrosine hydroxylase activity [2]. The transgenic mice expressing mutant A53T α-Syn were constructed for PD study [4,5,6,7,8,9,10,11,12]. These transgenic model with over-expression of wild type or A53T α-Syn showed PD-like symptoms and synaptic impairment [4, 9, 10, 1320]. The hemizygous Prnp-SNCA*A53T mice mixed with C57BL/6J×C3H, were found the elevated www.impactjournals.com/oncotarget

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