Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of -Synuclein

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• 作者：Eui-Nam Lee ; Hyun-Ju Cho ; Choong-Hwan Lee ; Daekyun Lee ; Kwang Chul Chung ; and Seung R. Paik
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：March 30, 2004
• 年：2004
• 卷：43
• 期：12
• 页码：3704 - 3715
• 全文大小：372K
• 年卷期：v.43,no.12(March 30, 2004)
• ISSN：1520-4995

文摘

-Synuclein is a pathological component of Parkinson's disease by constituting the filamentouscomponent of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of -synuclein have beenexamined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu²⁺) caused the self-oligomerization of -synuclein while Pc-Cu²⁺ did not affect the protein, indicating that introduction ofthe sulfonate groups was critical for the selective protein interaction. The PcTS-Cu²⁺ interaction with-synuclein has occurred predominantly at the N-terminal region of the protein with a K_d of 0.83 Mapart from the hydrophobic NAC (non-A component of Alzheimer's disease amyloid) segment.Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinitytoward -synuclein with a K_d of 3.12 M, and its binding site, on the other hand, was located at theacidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu²⁺ toward -synucleinresulted in distinctive features on the kinetics of protein aggregation, morphologies of the final aggregates,and their in vitro cytotoxicities. The PcTS actually suppressed the fibrous amyloid formation of -synuclein,but it produced the chopped-wood-looking protein aggregates. The aggregates showed rather low toxicity(9.5%) on human neuroblastoma cells (SH-SY5Y). In fact, the PcTS was shown to effectively rescue thecell death of -synuclein overexpressing cells caused by the lactacystin treatment as a proteasome inhibitor.The anti-aggregative and anti-amyloidogenic properties of PcTS were also demonstrated with alcoholdehydrogenase, glutathione S-transferase, and amyloid /A4 protein under their aggregative conditions.The PcTS-Cu²⁺, on the other hand, promoted the protein aggregation of -synuclein, which gave rise tothe fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the dataprovided in this study indicate that PcTS/PcTS-Cu²⁺ could be considered as possible candidates for thedevelopment of therapeutic or prophylactic strategies against the -synuclein-related neurodegenerativedisorders.