title: Chronic mild stress accelerates the progression of Parkinson's disease in A53T α-synuclein transgenic mice.
abstract: Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice). We show that when exposed to CMS, male, but not female, A53T Tg mice developed profound motor disabilities and exhibited olfactory sensitivity deficits. Pathological analysis also identified robust dopaminergic neuron degeneration and strong reduction of dopamine levels in A53T Tg male mice who underwent CMS treatment. Systematic examination of the abnormal aggregation of α-synuclein revealed a profound increase of inclusion in A53T Tg male mice subject to CMS resembling key pathological changes of PD. An insight into the mechanism underlying stress leading to the acceleration of neurodegeneration in those with genetic susceptibility, was revealed by evidence of microglia activation and elevated pro-inflammatory factor levels in A53T Tg male mice following CMS. Notably, these effects of CMS on the pathogenesis of PD showed a remarkable sexual dimorphism: only male A53T Tg mice exhibited exacerbation of the progression of PD. However, the molecular and cellular bases for this difference remains to be elucidated. Our results indicate a causative role for chronic mild stress using a PD animal model. Based on these findings, we propose that CMS acts as an environmental risk factor that leads to neuroinflammation and progressive neurodegeneration on a background of PD susceptibility.
authors.affiliation: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Qimei
authors.initials: Q
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Electronic address: lyfeng@simm.ac.cn.
authors.forename: Linyin
authors.initials: L
authors.lastname: Feng
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005518:Food Preferences; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D018377:Neurotransmitter Agents / Q000378:metabolism; D000857:Olfaction Disorders / Q000209:etiology / Q000235:genetics; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D013378:Substantia Nigra / Q000473:pathology; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D016138:Walking; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D016207:Cytokines; D018377:Neurotransmitter Agents; D025801:Ubiquitin; D051844:alpha-Synuclein; D003345:Corticosterone
keywords: Chronic mild stress; Dopamine; Microglia; Parkinson's disease; α-synuclein