Metal2Based Therapeutic Strategies of Neurodegenerative Diseases

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1 PROGRESS IN CHEMISTRY Vol. 21 No. 5 May, ( ),,, ;,, : O614 ; R741 : A : X(2009) Metal2Based Therapeutic Strategies of Neurodegenerative Diseases Zhang Shibing Wang Ying Liu Changlin 3 3 ( Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal University,Wuhan , China) Abstract The role of metal ions in both the pathology of neurodegenerative diseases and their treatments are summarized. The metal ion2mediated protein aggregation and oxidative stress in such as Alzheimer s and Parkinson s are discussed by integrating our preliminary data. The progress obtained to date shows that the metal chelation might be a preferred strategy in treatments of neurodegenerative diseases. Thus, a number of metal2chelating agents have been introduced into clinical trials. The alkylation of metal binding sites in the disease2linked proteins can significantly inhibit the formation of protein aggregates and reactive oxygen species, suggesting that this strategy may be a potential method to treat the diseases. Key words neurodegenerative diseases ; oxidative stress ; protein aggregation ; metal ions ; metal chelator Contents 1 Introduction 2 Brain metal ions and maintenance of their homeostasis 3 Metal ion2induced protein aggregation and oxidative stress 4 Protein aggregation and oxidative stress in Alzheimer s disease 5 Oxidative stress and 2synuclein aggregation in Parkinson s disease 6 Other neurodegenerative diseases 7 Therapeutic strategies 8 Conclusions 1 : ( ) 3 (No ) (No A04) 3 3 e2mail ccnu. edu. cn

2 (, AD) (PD) (ALS), AD PD,65 10 %,85 50 %, AD, AD 500, 1Π4,, 21 [1 ],,, [2,3 ] AD (senile plaque), (A ),, Cu 2 + (0144mmol L - 1 ) Zn 2 + (1mmol L - 1 ) Fe 3 + (1mmol L - 1 ) [4,5 ], AD, A, [6 9 ] Zn 2 +, Zn 2 + [5 ], Cu 2 + A ( 1) Zn 2 + Znt3,, Zn 2 +, Zn mol L - 1 Cu 2 +, 15 mol L - 1 A Zn 2 + Cu 2 +, 23 (MT3), A, AD MT3 [12 ] 2, Na + K + [5 ],Ca 2 +,, [10 ] Zn 2 + Cu 2 + Fe 3 +, Cu 2 +, Zn 2 +, Zn 2 +,,, ZnT Zip,, Zn mol L - 1 [11 ], Cu 2 + [16 ] Cu % 15 %,, Zn 2 +, Zn 2 +, 015 mol L - 1 [14 ],, Zn mol L - 1 [12,14 ] 1 Zn 2 + Cu 2 + A [12 ] Fig. 1 Zn 2 + and Cu 2 + interaction with A in glutamatergic synapse [12 ], [5 ] Zn 2 +, ATP, ATP7a ATP7b, ATP7a,ATP7a ATP7b Menkes (Wilson ) [17 ],Cu 2 + mol

3 5 905,, AD [4,5 ] [17 ], [18 ], AD PD (substantia nigra, SN) [12,13 ], PD SN [12,19 ], Cu 2 +, 2m Cu 2 + [24 ] 3 AD PD ALS,, AD A PD 2synuclein ALS (SOD1), NMR X, : (1), ; (2) ; (3) 5 13nm, ( ),, [20,21 ], ( ), [22,23 ],, 2 22 ( 2m) Cu 2 +, Cu 2 +, 2m ( ) ( 2a) ;Cu 2 + 2m (Cu ), ; Cu 2 +, 2m (Cu ), 1h, ( 2b c) 2m Cu 2 +, EDTA, 2 Cu 2 + 2m [24 ] Fig. 2 A model of Cu 2 + 2induced 2m amyloid aggregation [24 ],, Cu 2 + Zn 2 + A, A ; SOD1, Cu 2 + Zn 2 + ;Fe 3 + A [25 ] ; Ca 2 + A, 8 mol L - 1 Zn 2 + A ( 3), 3 (a) (b) 50 mol L mol L - 1 A Zn 2 + Zn 2 + Zn 2 +, Zn 2 + [26 ] Fe 3 + Cu 2 + Zn 2 +,,,,,,,DNA SOD1 ;, DNA EDTA,SOD1

4 A Zn 2 + [26 ] Fig. 3 Amorphous aggregates of A due to interaction with Zn 2 + [26 ] [27 ],, [28 ] 4 (AD) A Tau, A,Tau [5 ] A A 1 40 A 1 42, kD,A 1 42 A 1 40, A 1 42 A 1 40 ( EPR), A 1 40 Cu 2 +, ( 4a), Cu 2 + A 1 40, Cu 2 + ( 4b) [16 ], SOD1 A 1 40 Cu 2 + [29 ], EPR, Cu 2 + A 1 40, : Cu mol L - 1, AD 390 mol L - 1 ; Zn mol L mol L - 1 ; Fe mol L mol L - 1 [30 ], A, A,,, A A, Fe 3 +, Cu 2 + Zn 2 + A,, Cu 2 + Zn 2 + A [8 ] AD [31 ], A, (ROS), A Cu 2 + Fe 3 + A ; Zn 2 +, [32,33 ],,Zn 2 + A [15 ] A Cu 2 + Fe 3 + [6 ] ROS, H 2 O 2, Fenton HO Fe 2+ + H 2 O 2 Fe 3+ + HO + OH - A Cu 2 + ROS ( 5), A Cu 2 + Cu +, A : Cu Cu + O 2 O 2 2 -, H 2 O 2,A Zn 2 + Cu 2 + H 2 O 2 [6 ] Cu 2 + A,NMR A 4 Cu 2 + A (a) (b) [16 ] Fig. 4 Proposed mononuclear (a) and dinuclear (b) structures of Cu 2 + bound to A peptides [16 ], Fe 3 + Zn 2 + Cu 2 + AD AD 5 A Cu 2 + H 2 O 2 [6 ] Fig. 5 A model for catalytic H 2 O 2 production by A interaction with Cu 2 + [6 ]

5 5 907 [34 ] 5 2synuclein, [5 ], [35 ], Fe 3 + ΠFe 2 + PD ( ), Fe 3 + [36 ],, [37 PD 40 ],, SOD1 Fe 3 +, ( ) [41 ],,, (Lewy body) PD, 2synuclein Fe 3 + 2synuclein 140, 14kD, 3 : (1) (1 60), 4 ( XKTKEGVXXXX),, ; (2) NAC (61 95),, ; (3) (96 140),,,, 2synuclein [42,43 ], 2synuclein,,,, 2synuclein [43 ], [44 ] 2Synuclein Zn 2 + Fe 3 + Cu 2 +, [45 ] 2synuclein A, [46,47 ], 2synuclein, 2 synuclein ROS [48 ] 6 ALS, PrP [49 ] ALS,, 100 SOD1 ALS [50 ], : SOD1? DNA RNA, SOD1,, [51 ] 7,,,,,,,,,,, [52 ] ;, [5,28 ], ( 6),,desferrioxamine,82, (clioquinol, CQ) 82 [52 ], Cu 2 + CQ A, CQ A (Cu 2 + Zn 2 + ), A [5,16 ] CQ A [5 ],CQ [52 ],,

6 Fig. 6 Potential metal chelators of the past and the future Desferrioxamine (DFO),,DFO,, [52 ], 82 ( bis282 hydroxyquinaldine), [53 ],82 A H 2 O 2, H 2 GL 1 ΠH 2 GL 2, [52 ] H 2 GL 1 ΠH 2 GL 2 Cu 2 + Zn 2 + Cu 2 + Zn 2 + A, [52 ] A (Cu 2 + Zn 2 + Fe 3 + ) Tyr210 His26 His213 His214 Met235, A 2 A 2, A [4,29 ], A,,, Barnham Pt2 ( 7a) A [54 ], DNA,, DNA,, A His Phe Tyr 2 Pt2His, Pt His Pt Met235 ( Phe Tyr), Pt His26 His213 His214, NMR (CD) His, Met235 Thioflavin T (ThT) Pt2 A ; Pt2 A :Cu H 2 O 2 7 (a) Pt2 ; (b) Pt2 A 1 42 [54 ] Fig. 7 The structures of cisplatin and L2PtCl 2 complexes (a) and inhibition of A induced neurotoxicity (b) [54 ]

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