Alpha-synuclein is a pathological component of
Parkinson's disease by constituting the filamentous component of Lewy bodies.
Phthalocyanine (Pc) effects on the
amyloidosis of
alpha-synuclein have been examined. The
copper complex of
phthalocyanine tetrasulfonate (PcTS-Cu(2+)) caused the self-oligomerization of
alpha-synuclein while Pc-Cu(2+) did not affect the
protein, indicating that introduction of the sulfonate groups was critical for the selective
protein interaction. The PcTS-Cu(2+) interaction with
alpha-synuclein has occurred predominantly at the N-terminal region of the
protein with a K(d) of 0.83 microM apart from the hydrophobic NAC (non-Abeta component of
Alzheimer's disease amyloid) segment.
Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated
copper ion also showed a considerable affinity toward
alpha-synuclein with a K(d) of 3.12 microM, 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
alpha-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
alpha-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
alpha-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 beta/A4
protein under their aggregative conditions. The PcTS-Cu(2+), on the other hand, promoted the
protein aggregation of
alpha-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
alpha-synuclein-related
neurodegenerative disorders.