Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with motor symptoms and a plethora of non-motor and neuropsychiatric features that accompany the disease from prodromal to advanced stages. While several genetic defects have been identified in familial forms of PD, the predominance of cases are sporadic and result from a complex interplay of genetic and non-genetic factors. Clinical evidence, moreover, indicates a role of environmental stress in PD, supported by analogies between stress-induced pathological consequences and neuronal deterioration observed in PD. From this perspective, we set out to investigate the effects of chronic stress exposure in the context of PD by using a genetic mouse model that overexpresses human wildtype SNCA. Mimicking chronic stress was achieved by adapting a chronic unpredictable mild stress protocol (CUMS) comprising eight different stressors that were applied randomly over a period of eight weeks starting at an age of four months. A distinctive stress response with an impact on anxiety-related behavior was observed upon SNCA overexpression and CUMS exposure. SNCA-overexpressing mice showed prolonged elevation of cortisol metabolites during CUMS exposure, altered anxiety-related traits, and declined motor skills surfacing with advanced age. To relate our phenotypic observations to molecular events, we profiled the striatal and hippocampal transcriptome and used a 2 × 2 factorial design opposing genotype and environment to determine differentially expressed genes. Disturbed striatal gene expression and minor hippocampal gene expression changes were observed in SNCA-overexpressing mice at six months of age. Irrespective of the CUMS-exposure, genes attributed to the terms neuroinflammation, Parkinson’s signaling, and plasticity of synapses were altered in the striatum of SNCA-overexpressing mice.
Highlights
Parkinson’s disease (PD) is a slowly progressive neurodegenerative movement disorder with age being its strongest risk factor (de Lau and Breteler, 2006; Emamzadeh and Surguchov, 2018)
Commonalities between stress-triggered pathological consequences and the neuronal atrophy observed in PD and other neurodegenerative diseases, suggest stress as an environmental risk factor associated with onset and progression of neurodegeneration (Smith et al, 2002)
Whereas body weight developed in WT and TG in standard environment (Figure 1E), chronic unpredictable mild stress protocol (CUMS) led to differential weight development in WTST and TGST starting at 3 days of stress exposure and throughout the stress period (n = 23–25)
Summary
Parkinson’s disease (PD) is a slowly progressive neurodegenerative movement disorder with age being its strongest risk factor (de Lau and Breteler, 2006; Emamzadeh and Surguchov, 2018). The initial observations of neuronal damage and synaptic dysfunction after stress exposure (Uno et al, 1989; Mizoguchi et al, 2000; DiasFerreira et al, 2009) are supported by clinical studies indicating a role for stress (early and chronic) and elevated glucocorticoids in age-related disorders like Alzheimer’s disease (AD), PD, and dementia (Borenstein et al, 2006; Simard et al, 2009; Rothman and Mattson, 2010; Zou et al, 2013) In accordance with these findings, experimental studies with toxin-induced models show that stress accelerates neurodegeneration and aggravates motor symptoms (Pienaar et al, 2008; Smith et al, 2008; Lauretti et al, 2016). Such effects are believed to elicit from modulation of the dopaminergic system including the limbic circuitry upon stress exposure
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