Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of α-Synuclein

Eui Nam Lee, Hyun Ju Cho, Choong Hwan Lee, Daekyun Lee, Kwang Chul Chung, Seung R. Paik

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

α-Synuclein is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of α-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu2+) caused the self-oligomerization of α-synuclein while Pc-Cu2+ did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu2+ interaction with α-synuclein has occurred predominantly at the N-terminal region of the protein with a Kd of 0.83 μM apart from the hydrophobic NAC (non-Aβ component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward α-synuclein with a Kd of 3.12 μM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu 2+ toward α-synuclein resulted 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 α-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 the cell death of α-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 alcohol dehydrogenase, glutathione S-transferase, and amyloid β/A4 protein under their aggregative conditions. The PcTS-Cu2+, on the other hand, promoted the protein aggregation of α-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu 2+ could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the α-synuclein-related neurodegenerative disorders.

Original languageEnglish
Pages (from-to)3704-3715
Number of pages12
JournalBiochemistry
Volume43
Issue number12
DOIs
Publication statusPublished - 2004 Mar 30

Fingerprint

Synucleins
Cytotoxicity
Amyloid
Proteins
tetrasulfophthalocyanine
Copper
Agglomeration
Lewy Bodies
Oligomerization
Proteasome Inhibitors
Alcohol Dehydrogenase
Amyloid beta-Peptides
Amyloidosis
Cell death
Glutathione Transferase
Neuroblastoma
Neurodegenerative Diseases

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Lee, Eui Nam ; Cho, Hyun Ju ; Lee, Choong Hwan ; Lee, Daekyun ; Chung, Kwang Chul ; Paik, Seung R. / Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of α-Synuclein. In: Biochemistry. 2004 ; Vol. 43, No. 12. pp. 3704-3715.
@article{03ef0b5dd9cc40c68e4670d51534fbd0,
title = "Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of α-Synuclein",
abstract = "α-Synuclein is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of α-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu2+) caused the self-oligomerization of α-synuclein while Pc-Cu2+ did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu2+ interaction with α-synuclein has occurred predominantly at the N-terminal region of the protein with a Kd of 0.83 μM apart from the hydrophobic NAC (non-Aβ component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward α-synuclein with a Kd of 3.12 μM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu 2+ toward α-synuclein resulted 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 α-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 the cell death of α-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 alcohol dehydrogenase, glutathione S-transferase, and amyloid β/A4 protein under their aggregative conditions. The PcTS-Cu2+, on the other hand, promoted the protein aggregation of α-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8{\%}. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu 2+ could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the α-synuclein-related neurodegenerative disorders.",
author = "Lee, {Eui Nam} and Cho, {Hyun Ju} and Lee, {Choong Hwan} and Daekyun Lee and Chung, {Kwang Chul} and Paik, {Seung R.}",
year = "2004",
month = "3",
day = "30",
doi = "10.1021/bi0356707",
language = "English",
volume = "43",
pages = "3704--3715",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "12",

}

Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of α-Synuclein. / Lee, Eui Nam; Cho, Hyun Ju; Lee, Choong Hwan; Lee, Daekyun; Chung, Kwang Chul; Paik, Seung R.

In: Biochemistry, Vol. 43, No. 12, 30.03.2004, p. 3704-3715.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phthalocyanine Tetrasulfonates Affect the Amyloid Formation and Cytotoxicity of α-Synuclein

AU - Lee, Eui Nam

AU - Cho, Hyun Ju

AU - Lee, Choong Hwan

AU - Lee, Daekyun

AU - Chung, Kwang Chul

AU - Paik, Seung R.

PY - 2004/3/30

Y1 - 2004/3/30

N2 - α-Synuclein is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of α-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu2+) caused the self-oligomerization of α-synuclein while Pc-Cu2+ did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu2+ interaction with α-synuclein has occurred predominantly at the N-terminal region of the protein with a Kd of 0.83 μM apart from the hydrophobic NAC (non-Aβ component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward α-synuclein with a Kd of 3.12 μM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu 2+ toward α-synuclein resulted 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 α-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 the cell death of α-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 alcohol dehydrogenase, glutathione S-transferase, and amyloid β/A4 protein under their aggregative conditions. The PcTS-Cu2+, on the other hand, promoted the protein aggregation of α-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu 2+ could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the α-synuclein-related neurodegenerative disorders.

AB - α-Synuclein is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of α-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu2+) caused the self-oligomerization of α-synuclein while Pc-Cu2+ did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu2+ interaction with α-synuclein has occurred predominantly at the N-terminal region of the protein with a Kd of 0.83 μM apart from the hydrophobic NAC (non-Aβ component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward α-synuclein with a Kd of 3.12 μM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu 2+ toward α-synuclein resulted 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 α-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 the cell death of α-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 alcohol dehydrogenase, glutathione S-transferase, and amyloid β/A4 protein under their aggregative conditions. The PcTS-Cu2+, on the other hand, promoted the protein aggregation of α-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu 2+ could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the α-synuclein-related neurodegenerative disorders.

UR - http://www.scopus.com/inward/record.url?scp=1642372780&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642372780&partnerID=8YFLogxK

U2 - 10.1021/bi0356707

DO - 10.1021/bi0356707

M3 - Article

C2 - 15035641

AN - SCOPUS:1642372780

VL - 43

SP - 3704

EP - 3715

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 12

ER -