Endogenous catecholamine enhances the dysfunction of unfolded protein response and alpha-synuclein oligomerization in PC12 cells overexpressing human alpha-synuclein.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies. Recently, many studies have focused on the interaction between alpha-synuclein and catecholamine in the pathogenesis of PD. However, no detailed relationship between cathecholamine and alpha-synuclein cytotoxicity has been elucidated. Therefore, this study established PC12 cell lines which overexpress human alpha-synuclein in a tetracycline-inducible manner. The overexpression of human alpha-synuclein increased the number of apoptotic cells in a long-term culture. Moreover, human alpha-synuclein expressing PC12 cells demonstrated an increased vulnerability to several stressors in a short culture period. Thapsigargin increased the SDS soluble oligomers of alpha-synuclein associated with catecholamine-quinone. The unfolded protein response (UPR) study showed that thapsigargin increased eIF2alpha phosphorylation and nuclear GADD153/CHOP induction under alpha-synuclein overexpressed conditions. The activities of the ATF6alpha and IRE1alpha pathways decreased. These findings suggest that an overexpression of alpha-synuclein partly inactivates the UPR. alpha-Methyltyrosine inhibited the dysfunction of the UPR caused by an overexpression of human alpha-synuclein. Therefore, these findings suggest that the coexistence of human alpha-synuclein with catecholamine enhances the endoplasmic reticulum stress-related toxicity in PD pathogenesis.
Ito
Satoru
S
Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Japan. s-itou@med.tottori-u.ac.jp
Nakaso
Kazuhiro
K
Imamura
Keiko
K
Takeshima
Takao
T
Nakashima
Kenji
K
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019805:alpha-Methyltyrosine / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D051846:beta-Synuclein / Q000235:genetics / Q000378:metabolism
D002395:Catecholamines; D004791:Enzyme Inhibitors; D014157:Transcription Factors; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051742:Transcription Factor CHOP; C101003:ELF2 protein, human; D019805:alpha-Methyltyrosine; D019284:Thapsigargin; D020932:Nerve Growth Factor