The role of chronic stress on the development of Parkinson's Disease phenotype

Background Depression and anxiety, which are associated with chronic stress are core features of Parkinson's Disease (PD). Stress is suggested to affect onset and prognosis of PD. In this study, it had been hypothesized that exposure to chronic stress would lead to earlier onset of motor and non-motor symptoms of Parkinson's Disease (PD). Also, mice with PINK1-/- genotype would be more vulnerable to the effects of chronic stress in this manner. Methods To test this hypothesis, C57BL/6 Non-stress exposed (n=8), C57BL/6 Stress-exposed (n=11), PINK1-/- Non-stress exposed (n=6), PINK1-/- Stress-exposed (n=10), C57BL/6 Follow-up Non-stress exposed (n=16), PINK1-/- Follow-up Non-stress exposed (n=13) and PINK1-/- Follow-up Stress-exposed (n=6) groups were used. For stress-exposed groups, a chronic stress paradigm with three different stressors as rat exposure, tail suspension and restraint stress for the first 28 consecutive days were used. Behavioral tests were applied to assess anxiety (elevated plus maze), memory (spontaneous alternation test), and motor functions (grip and pole tests). The effect of aging in addition to chronic stress exposure was evaluated using both PINK1-/- and control mice aged for six more months. As a validation of the chronic stress procedure, adrenal gland weight, animal weight and plasma corticosterone levels were measured. Results It was found that chronic stress paradigm that was used, lead to significant weight differences, and increased relative adrenal gland weight. Weight at the 4th week was significantly increased by PINK1-/- genotype (B=2.875, p<0.001) and decreased by stress exposure (B=-1.982, p=0.003), when genotype and stress exposure were analyzed as factors in a multivariate linear regression model [F(2,69)=13.11, R2= 0.281, p<0.001]. When relative adrenal gland weights of the groups that were terminated after the first month were compared, it had been found that it was significantly increased by stress (B=3.587e-5, p=<0.001) but it did not depend on genotype (B=-3.961e-6, p=0.679), when genotype and stress exposure were analyzed as factors in a multivariate linear regression model [F(2,34)=6.943, R2=0.303, p=0.003]. When PINK1-/- follow-up non-stress exposed, PINK1-/- follow-up stress-exposed and C57BL/6 follow-up non-stress exposed groups were compared, as expected PINK1-/- Follow-up Stress-exposed group had significantly higher relative adrenal weight than both PINK1-/- Follow-up Non-exposed (p=0.001) and C57BL/6 Follow-up Non-exposed (p<0.01) groups. In follow-up groups' comparison, PINK1-/- follow-up stress-exposed group was shown to have significantly higher plasma corticosterone levels than PINK1-/- follow-up non-stress-exposed group (p=0.046). In the anxiety level assessments of PINK1-/- non-stress exposed, C57 non-stress exposed, PINK1-/- stress-exposed and C57 stress-exposed groups, anxiety levels were found to be significantly increased by PINK1-/- genotype (B=-0.085, p=0.003; B=0.099, p<0.001) but not depend on stress exposure (B=0.043, p=0.129; B=-0.025, p=0.322), when genotype and stress exposure were analyzed as factors in a multivariate linear model in both EPM ratio time [F(2,69)=5.552, R2=0.142, p=0.006] and number [F(2,69)=7.974, R2=0.192, p<0.001] respectively. In motor function assessments of PINK1-/- non-stress exposed, C57 non-stress exposed, PINK1-/- stress-exposed and C57 stress-exposed groups, required time to descent was found to be increased with stress exposure (B=3.555, p=0.022), but not depend on PINK1-/- genotype (B=-2.581, p=0.086); and required time to descent after rotation was found to be increased with both stress exposure (B=1.4, p=0.004) and with having C57BL/6 genotype (B=-1.255, p=0.007), when genotype and stress exposure were analyzed as factors in a multivariate linear model in time spent to descent [F(2,69)=3.743, R2=0.101, p=0.029] and time spent to descent after rotation [F(2,69)=7.3, R2=0.179, p=0.001] in the pole test. To assess effects of aging on psychopathology, mixed-effect regression analysis was used to compare PINK1-/- Follow up Non-stress exposed and Stress-exposed groups' 1st and 6th-month assessments by controlling for both time and stress effect and using animal IDs as cluster variable. EPM ratio number results were indicated that anxiety level was increased by stress (B=0.0501, p=0.015) and decreased by time (B=-0.0463, p=0.009). In grip test results, the time span of holding the wire is found to be decreased by time (B=-53.9, p=0.003). In the comparison of C57BL/6 Follow-up Non-stress exposed, PINK1-/- Follow-up Non-stress exposed and PINK1-/- Follow-up Stress-exposed groups, it was found that PINK1-/- Follow-up Stress-exposed group took longer time to rotate downward than both C57BL/6 Follow-up Non-stress exposed (p=0.021) and PINK1-/- Follow-up Non-stress exposed groups (p=0.029). Additionally, both PINK1 Follow-up Stress-exposed (p=0.001) and PINK1-/- Follow-up Non-stress exposed (p<0.001) groups were required higher distance to rotate than C57BL/6 Follow-up Non-stress exposed group. Conclusions These findings support that genetic predisposition to PD could lead to vulnerability for psychiatric symptomatology despite stress exposure and that chronic stress exposure may not lead to earlier onset of motor symptoms.