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.
Highlights
Parkinson’s disease (PD) is currently regarded as the most common neurodegenerative disorder following Alzheimer’s disease, that affects over 5 million people worldwide and 1–3% of people over 50 years of age (Meissner et al, 2011; Lashuel et al, 2013)
We determined that the chronic injection of MPTP and probenecid (MPTP/p) caused olfactory deficit by performing the buried food test and short-term olfactory memory test; thermal hyperalgesia by the hot plate test; neuropsychiatric features by the open field test and tail suspension test; cognitive decline by the Y maze test and novel object recognition test; gastrointestinal dysfunction by the bead expulsion test and one-h stool collection test
The chronic injection of MPTP/p resulted in high expression levels of α-synuclein in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, and colon, and low expression levels of TH in striatum and substantia nigra
Summary
Parkinson’s disease (PD) is currently regarded as the most common neurodegenerative disorder following Alzheimer’s disease, that affects over 5 million people worldwide and 1–3% of people over 50 years of age (Meissner et al, 2011; Lashuel et al, 2013). PD is mainly characterized by motor deficits including tremor or rigidity (Dauer and Przedborski, 2003). These motor deficits result from severe loss of dopaminergic nigrostriatal neurons (Maiti et al, 2017). A wide range of non-motor symptoms such as olfactory deficit or cognitive decline is known to be strongly associated with PD pathological processes and significantly affect the quality of life of PD patients (Schapira et al, 2017; Monastero et al, 2018; Liu et al, 2020). One of phosphorylated forms of α-synuclein, pS129, is significantly correlated with PD severity (Wang et al, 2012; Stewart et al, 2015)
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