Browsing by Subject "Parkinson Disease / genetics"
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Item Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units(Springer Nature, 2017-06-01) Zou, Jing; Chen, Zhaoyu; Wei, Xiaobo; Chen, Zhigang; Fu, Yongmei; Yang, Xiaoyan; Chen, Dan; Wang, Rui; Jenner, Peter; Lu, Jia-Hong; Li, Min; Zhang, Zhuohua; Tang, Beisha; Jin, Kunlin; Wang, QingCystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T alpha-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-alpha/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.Item Establishing Equivalent Aerobic Exercise Parameters Between Early-Stage Parkinson's Disease and Pink1 Knockout Rats(IOS Press, 2022-06-28) Salvatore, Michael F.; Soto, Isabel; Kasanga, Ella A.; James, Rachael; Shifflet, Marla K.; Doshier, Kirby; Little, Joel T.; John, Joshia; Alphonso, Helene M.; Cunningham, J. Thomas; Nejtek, Vicki A.BACKGROUND: Rodent Parkinson's disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. OBJECTIVE: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. METHOD: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr /=3 months, >/=3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. RESULTS: After completing aerobic exercise for approximately 30 min, PD subjects had increased HR approximately 35% above baseline ( approximately 63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naive PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8-10 m/min increased HR up to 25% above baseline ( approximately 67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naive cohort at 5 months old. CONCLUSION: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.