The Role of Prolonged ER Stress and PERK/EIF2⍺/ATF4 Pathway in the Pathogenesis of Parkinson Disease
Introduction. Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and presence of alpha-synuclein (⍺S) aggregates forming intracellular inclusions1,6. The pathogenesis of the selective loss of dopamine neurons and accumulation of alpha-synuclein remains unclear; however, recent evidence suggests the activation of PERK/ATF4 pathway within the unfolded protein response (UPR) by ER stress is a causative factor of PD resulting in neurodegeneration4-6. Studies have found up-regulation of ATF4 will launch a pro-apoptotic death in dopamine neurons of the SNpc in rat models with Parkinson-like neurodegeneration induced by human alpha-synuclein overexpression2. Methods. Rat models were injected with the rAAV vector gene to express GFP, human wildtype alpha-synuclein, ATF4, or both alpha-synuclein and ATF4 simultaneously in the SNpc. Striatal and nigral tissues were dissected from the injected animal models at 4 and 8 weeks to be processed for immunohistochemistry and western blot analysis. Furthermore, levels of protein expression were quantified through western blot analysis and a caspase 3/7 activity assay was also performed from intact un-injected brains and rat models injected with ATF4 expressing virus. Results. Increased ATF4 expression was observed in rAAV-ATF4 and rAAV-⍺S + ATF4 injected models. Significant findings also reveal a similar increase in ATF4 expression in animal models overexpressing only exogenous ⍺S, thus, results confirm ATF4 up-regulation is due to human ⍺S overexpression in the SNpc of rat models2. Studies show ⍺S overexpression significantly reduced the percentage of TH-positive cells and dopamine neurons compared to control GFP models2. Additionally, the co-expression of ATF4 and ⍺S did not decrease the loss of TH-positive cells and dopamine neuronal levels and further increased impairment. Overexpression of ATF4 alone and ATF4+⍺S also resulted in increased caspase 3/7 activity compared to GFP controls and un-injected intact animal models, indicating dopaminergic cell death occurs through apoptosis in response to ATF4 up-regulation2. Conclusions. Studies indicate ATF4 up-regulation does not protect nigral dopamine neurons against ER stress induced by overexpression of ⍺S pathology2,4. Moreover, PERK/ATF4 up-regulation plays a pinnacle role in dopaminergic cell death through apoptosis in the SNpc of PD patients2,7. The PERK/ATF4 pathway reveals a potential molecular pathogenic mechanism associated with the neurodegeneration in PD and possible therapeutic target for PD treatment3.
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