A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid

Na-Ra Han; Yu-Kang Kim; Sora Ahn; Tae-Yeon Hwang; Hyejung Lee; Hi-Joon Park

doi:10.3389/fnagi.2020.599045

A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid

Front Aging Neurosci. 2021 Jan 13:12:599045. doi: 10.3389/fnagi.2020.599045. eCollection 2020.

Authors

Na-Ra Han^{1

2}, Yu-Kang Kim^{1

2}, Sora Ahn¹, Tae-Yeon Hwang^{1

3}, Hyejung Lee³, Hi-Joon Park^{1

2}

Affiliations

¹ Integrative Parkinson's Disease Research Group, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, South Korea.
² Department of Anatomy & Information Sciences, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
³ Department of Meridian & Acupoints, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.

Abstract

Parkinson's disease (PD) is characterized by non-motor symptoms as well as motor deficits. The non-motor symptoms rarely appear individually and occur simultaneously with motor deficits or independently. However, a comprehensive research on the non-motor symptoms using an experimental model of PD remains poorly understood. The aim of the current study is to establish a chronic mouse model of PD mimicking the comprehensive non-motor symptoms of human PD by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/p). The non-motor and motor symptoms were evaluated by performing buried food, short-term olfactory memory, hot plate, open field, tail suspension, Y maze, novel object recognition, bead expulsion, one-h stool collection, rotarod, rearing, catalepsy, and akinesia tests after 10 injections of MPTP/p into mice. The expression levels of α-synuclein, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) or DJ-1 were analyzed by Western blotting or immunostaining. MPTP/p-treated mice achieved to reproduce the key features of non-motor symptoms including olfactory deficit, thermal hyperalgesia, anxiety, depression, cognitive decline, and gastrointestinal dysfunction in addition to motor deficits. The MPTP/p-treated mice also showed the high levels of α-synuclein and low levels of TH and DJ-1 in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, or colon. In addition, the expression levels of phosphorylated-α-synuclein and GFAP were elevated in the striatum and substantia nigra in the MPTP/p-treated mice. Taken together, our study clarifies that the chronic MPTP/p-treated mice have a variety of non-motor dysfunctions as well as motor abnormalities by α-synuclein overexpression and dopaminergic depletion. Therefore, the study of comprehensive phenotypes of non-motor symptoms in one PD model would advance in-depth understandings of neuropathological alternations and contribute to future strategies for PD treatment.

Keywords: 1-methyl-4-phenyl-1; 2; 3; 6-tetrahydropyridine and probenecid; Parkinson’s disease; behavior tests; non-motor symptoms; α-synuclein.