Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner

An-Di Chen; Jia-Xin Cao; Hai-Chao Chen; Hong-Li Du; Xiao-Xia Xi; Jing Sun; Jie Yin; Yu-Hong Jing; Li-Ping Gao

doi:10.3389/fnagi.2022.842380

Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner

Front Aging Neurosci. 2022 Aug 8:14:842380. doi: 10.3389/fnagi.2022.842380. eCollection 2022.

Authors

An-Di Chen^{1

2}, Jia-Xin Cao¹, Hai-Chao Chen¹, Hong-Li Du², Xiao-Xia Xi³, Jing Sun³, Jie Yin¹, Yu-Hong Jing^{1

4}, Li-Ping Gao²

Affiliations

¹ Institute of Anatomy and Histology & Embryology, Neuroscience, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
² Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
³ Center of Experimental Animal, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
⁴ Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

Abstract

Multiple factors such as genes, environment, and age are involved in developing Parkinson's disease (PD) pathology. However, how various factors interact to cause PD remains unclear. Here, 3-month and 9-month-old hα-syn^+⁣/- mice were treated with low-dose rotenone for 2 months to explore the mechanisms that underline the environment-gene-age interaction in the occurrence of PD. We have examined the behavior of mice and the PD-like pathologies of the brain and gut. The present results showed that impairments of the motor function and olfactory function were more serious in old hα-syn^+/- mice with rotenone than that in young mice. The dopaminergic neuron loss in the SNc is more in old hα-syn^+/- mice with rotenone than in young mice. Expression of hα-syn^+/- is increased in the SNc of hα-syn^+/- mice following rotenone treatment for 2 months. Furthermore, the number of activated microglia cells increased in SNc and accompanied the high expression of inflammatory cytokines, namely, TNF-α and IL-18 in the midbrain of old hα-syn^+/- mice treated with rotenone. Meanwhile, we found that after treatment with rotenone, hα-syn positive particles deposited in the intestinal wall, intestinal microflora, and T lymphocyte subtypes of Peyer's patches changed, and intestinal mucosal permeability increased. Moreover, these phenomena were age-dependent. These findings suggested that rotenone aggravated the PD-like pathologies and affected the brain and gut of human α-syn^+/- transgenic mice in an age-dependent manner.

Keywords: Parkinson’s disease; aging; brain–gut axis; human α-syn+/– (A53T); rotenone.