Dl-3-n-Butylphthalide Alleviates Behavioral and Cognitive Symptoms Via Modulating Mitochondrial Dynamics in the A53T-α-Synuclein Mouse Model of Parkinson's Disease.

Huiying Li,Manshi Wang,Ling Zhang,Hongquan Wang,Yanfeng Li

doi:10.3389/fnins.2021.647266

Abstract

BackgroundAggregation and neurotoxicity of the presynaptic protein α-synuclein and the progressive loss of nigral dopaminergic neurons are believed to be the key hallmarks of Parkinson’s disease (PD). A53T mutant α-synuclein causes early onset PD and more severe manifestations. A growing body of evidence shows that misfolding or deposition of α-synuclein is linked to the maintenance of mitochondrial dynamics, which has been proven to play an important role in the pathogenesis of PD. It has been observed that Dl-3-n-butylphthalide (NBP) may be safe and effective in improving the non-tremor-dominant PD. However, the potential mechanism remains unclear. This study aimed to investigate whether NBP could decrease the loss of dopaminergic neurons and α-synuclein deposition and explore its possible neuroprotective mechanisms.MethodsA total of 20 twelve-month-old human A53T α-synuclein transgenic mice and 10 matched adult C57BL/6 mice were included in the study; 10 adult C57BL/6 mice were selected as the control group and administered with saline (0.2 ml daily for 14 days); 20 human A53T α-synuclein transgenic mice were randomly divided into A53T group (treated in the same manner as in the control group) and A53T + NBP group (treated with NBP 0.2 ml daily for 14 days). Several markers of mitochondrial fission and fusion and mitophagy were determined, and the behavioral, olfactory, and cognitive symptoms were assessed as well.ResultsIn the present study, it was observed that the A53T-α-synuclein PD mice exhibited anxiety-like behavioral disturbance, impairment of coordination ability, memory deficits, and olfactory dysfunction, loss of dopaminergic neurons, and α-synuclein accumulation. Meanwhile, the mitofusin 1 expression was significantly decreased, and the mitochondrial number and dynamin-related protein 1, Parkin, and LC3 levels were increased. The detected levels of all markers were reversed by NBP treatment, and the mitochondrial morphology was partially recovered.ConclusionIn the present study, a valuable neuropharmacological role of NBP has been established in the A53T-α-synuclein PD mouse model. Possible neuroprotective mechanisms might be that NBP is involved in the maintenance of mitochondrial dynamics including mitochondrial fission and fusion and clearance of damaged mitochondria. It is essential to perform further experiments to shed light on the precise mechanisms of NBP on mitochondrial homeostasis.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, affecting up to 2% of the population over 65 years old (Ray et al, 2018)
Several lines of evidence show that misfolding or aggregation of α-synuclein is linked to the maintenance of mitochondrial dynamics including mitochondrial fusion–fission, transport, and mitophagy, which has been proven to play an important role in the pathogenesis of PD (Pozo Devoto and Falzone, 2017; Ordonez et al, 2018; Vicario et al, 2018), and this effect is prominent in α-synuclein at position 53 of the α-synuclein protein (A53T) mutation (Xie and Chung, 2012)
It was observed that the A53T-α-synuclein PD mice exhibited anxiety-like behavioral disturbance, impairment of coordination ability, memory deficits, and olfactory dysfunction

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, affecting up to 2% of the population over 65 years old (Ray et al, 2018). Besides the typical clinical motor symptoms, behavioral and cognitive symptoms and olfactory dysfunction are highly prevalent in PD. These non-motor symptoms may occur even in the prodromal stages of the disease, worsen with disease progression, and surpass motor symptoms as the major factors affecting the patient’s quality of life and the caregiver’s burden (Martinez-Martin et al, 2015; Prakash et al, 2016). It is urgent to identify the promising neuroprotective or disease-modifying drugs to alleviate these non-motor symptoms, slow down the progression of PD, or tackle the cause of the disease. This study aimed to investigate whether NBP could decrease the loss of dopaminergic neurons and α-synuclein deposition and explore its possible neuroprotective mechanisms

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