Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice

ACS Chemical Neuroscience

Volumn 7, Issue 1, 2016, Pages 119-129

  Finkelstein, David I ^a   Hare, Dominic J ^a,b,c   Billings, Jessica L ^a   Sedjahtera, Amelia ^a   Nurjono, Milawaty ^a   Arthofer, Elisa ^a,d   George, Sonia ^e   Culvenor, Janetta G ^e   Bush, Ashley I ^a   Adlard, Paul A ^a  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b UNIVERSITY OF TECHNOLOGY SYDNEY   (Australia)

^c MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^d KAROLINSKA INSTITUTE   (Sweden)

^e UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

A53T; alpha synuclein; Clioquinol; Parkinson's disease

Indexed keywords

ALPHA SYNUCLEIN; CENTRAL STIMULANT AGENT; CLIOQUINOL; FERRIC ION;

ALZHEIMER DISEASE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE DENSITY; CAUDATE NUCLEUS; CELL COUNT; CELL DENSITY; CELL LOSS; COGNITION; CONTROLLED STUDY; DENDRITE; DENDRITIC SPINE; DOPAMINERGIC SYSTEM; GENE MUTATION; GENE OVEREXPRESSION; GENOTYPE; HIPPOCAMPUS; HUMAN; MOLECULAR INTERACTION; MOTOR PERFORMANCE; MOUSE; NERVE CELL; NEUROANATOMY; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; RECOGNITION; SHORT COURSE THERAPY; SOLUBILIZATION; SPATIAL LEARNING; SPATIAL MEMORY; SUBSTANTIA NIGRA PARS COMPACTA; TREATMENT OUTCOME; TREATMENT RESPONSE; ANIMAL; BRAIN; COGNITION DISORDERS; DISEASE MODEL; DRUG EFFECTS; EXPLORATORY BEHAVIOR; GENETICS; MAZE TEST; METABOLISM; MOVEMENT DISORDERS; MUTATION; PATHOLOGY; PROTEIN AGGREGATION, PATHOLOGICAL; SILVER STAINING; TRANSGENIC MOUSE;

ALPHA-SYNUCLEIN; ANIMALS; BRAIN; CLIOQUINOL; COGNITION DISORDERS; DISEASE MODELS, ANIMAL; EXPLORATORY BEHAVIOR; HUMANS; MAZE LEARNING; MICE; MICE, TRANSGENIC; MOVEMENT DISORDERS; MUTATION; PROTEIN AGGREGATION, PATHOLOGICAL; RECOGNITION (PSYCHOLOGY); SILVER STAINING; SPATIAL LEARNING;

EID: 84955581925     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/acschemneuro.5b00253     Document Type: Article

References (100)

1. Kahle, P. (2008) J. alpha-synucleinopathy models and human neuropathology: similarities and differences Acta Neuropathol. 115, 87-95 10.1007/s00401-007-0302-x
2. Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions Nat. Cell Biol. 4, 160-164 10.1038/ncb748
3. Aarsland, D., Ballard, C. G., and Halliday, G. (2004) Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity? J. Geriatr. Psychiatry Neurol. 17, 137-145 10.1177/0891988704267470
4. Lippa, C. F., Duda, J. E., Grossman, M., Hurtig, H. I., Aarsland, D., Boeve, B. F., Brooks, D. J., Dickson, D. W., Dubois, B., Emre, M., Fahn, S., Farmer, J. M., Galasko, D., Galvin, J. E., Goetz, C. G., Growdon, J. H., Gwinn-Hardy, K. A., Hardy, J., Heutink, P., Iwatsubo, T., Kosaka, K., Lee, V. M., Leverenz, J. B., Masliah, E., McKeith, I. G., Nussbaum, R. L., Olanow, C. W., Ravina, B. M., Singleton, A. B., Tanner, C. M., Trojanowski, J. Q., and Wszolek, Z. K. (2007) DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers Neurology 68, 812-819 10.1212/01.wnl.0000256715.13907.d3
5. Masuda-Suzukake, M., Nonaka, T., Hosokawa, M., Oikawa, T., Arai, T., Akiyama, H., Mann, D. M., and Hasegawa, M. (2013) Prion-like spreading of pathological alpha-synuclein in brain Brain 136, 1128-1138 10.1093/brain/awt037
6. Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O'Brien, P., Trojanowski, J. Q., and Lee, V. M. (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice Science 338, 949-953 10.1126/science.1227157
7. Luk, K. C., Kehm, V. M., Zhang, B., O'Brien, P., Trojanowski, J. Q., and Lee, V. M. (2012) Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice J. Exp. Med. 209, 975-986 10.1084/jem.20112457
8. Kramer, M. L. and Schulz-Schaeffer, W. J. (2007) Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies J. Neurosci. 27, 1405-1410 10.1523/JNEUROSCI.4564-06.2007
9. Paleologou, K. E., Kragh, C. L., Mann, D. M., Salem, S. A., Al-Shami, R., Allsop, D., Hassan, A. H., Jensen, P. H., and El-Agnaf, O. M. (2009) Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies Brain 132, 1093-1101 10.1093/brain/awn349
10. Bartels, T., Choi, J. G., and Selkoe, D. J. (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation Nature 477, 107-110 10.1038/nature10324
11. Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q., and Lee, V. M. (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death Neuron 72, 57-71 10.1016/j.neuron.2011.08.033
12. Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A., Nishioka, K., Fuchs, J., Gasser, T., Maraganore, D. M., Adler, C. H., Larvor, L., Chartier-Harlin, M. C., Nilsson, C., Langston, J. W., Gwinn, K., Hattori, N., and Farrer, M. J. (2008) Genomic investigation of alpha-synuclein multiplication and parkinsonism Ann. Neurol. 63, 743-750 10.1002/ana.21380
13. Fuchs, J., Nilsson, C., Kachergus, J., Munz, M., Larsson, E. M., Schule, B., Langston, J. W., Middleton, F. A., Ross, O. A., Hulihan, M., Gasser, T., and Farrer, M. J. (2007) Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication Neurology 68, 916-922 10.1212/01.wnl.0000254458.17630.c5
14. Yamaguchi, K., Cochran, E. J., Murrell, J. R., Polymeropoulos, M. H., Shannon, K. M., Crowther, R. A., Goedert, M., and Ghetti, B. (2005) Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the alpha-synuclein gene Acta Neuropathol. 110, 298-305 10.1007/s00401-005-1042-4
15. Dettmer, U., Newman, A. J., Soldner, F., Luth, E. S., Kim, N. C., von Saucken, V. E., Sanderson, J. B., Jaenisch, R., Bartels, T., and Selkoe, D. (2015) Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation Nat. Commun. 6, 7314 10.1038/ncomms8314
16. Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G., and Hengerer, B. (2009) Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology J. Neurochem. 111, 192-203 10.1111/j.1471-4159.2009.06324.x
17. Uversky, V. N., Li, J., and Fink, A. L. (2001) Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein-A possible molecular link between Parkinson's disease and heavy metal exposure J. Biol. Chem. 276, 44284-44296 10.1074/jbc.M105343200
18. Dehay, B., Bourdenx, M., Gorry, P., Przedborski, S., Vila, M., Hunot, S., Singleton, A., Olanow, C. W., Merchant, K. M., Bezard, E., Petsko, G. A., and Meissner, W. G. (2015) Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations Lancet Neurol. 14, 855-866 10.1016/S1474-4422(15)00006-X
19. Zecca, L., Stroppolo, A., Gatti, A., Tampellini, D., Toscani, M., Gallorini, M., Giaveri, G., Arosio, P., Santambrogio, P., Fariello, R. G., et al. 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging Proc. Natl. Acad. Sci. U. S. A. 101, 9843 10.1073/pnas.0403495101
20. Hare, D. J., Arora, M., Jenkins, N. L., Finkelstein, D. I., Doble, P. A., and Bush, A. I. (2015) Is early-life iron exposure critical in neurodegeneration? Nat. Rev. Neurol. 11, 536-544 10.1038/nrneurol.2015.100
21. Gerlach, M., Double, K. L., Youdim, M., and Riederer, P. (2006) Potential sources of increased iron in the substantia nigra of parkinsonian patients J. Neural. Transm. Suppl. 70, 133-142 10.1007/978-3-211-45295-0-21
22. Kell, D. B. (2009) Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases BMC Med. Genomics 2, 2 10.1186/1755-8794-2-2
23. Ke, Y. and Ming Qian, Z. (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders Lancet Neurol. 2, 246-253 10.1016/S1474-4422(03)00353-3
24. Ayton, S. and Lei, P. (2014) Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration BioMed Res. Int. 2014, 581256 10.1155/2014/581256
25. Ayton, S., Lei, P., Adlard, P. A., Volitakis, I., Cherny, R. A., Bush, A. I., and Finkelstein, D. I. (2014) Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease Mol. Neurodegener. 9, 27 10.1186/1750-1326-9-27
26. Hare, D. J., Ayton, S., Bush, A., and Lei, P. A delicate balance: Iron metabolism and diseases of the brain Front. Aging Neurosci. 2013, 5. 10.3389/fnagi.2013.00034
27. Magaki, S., Raghavan, R., Mueller, C., Oberg, K. C., Vinters, H. V., and Kirsch, W. M. (2007) Iron, copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias Neurosci. Lett. 418, 72-76 10.1016/j.neulet.2007.02.077
28. Bareggi, S. R. and Cornelli, U. (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders CNS Neurosci. Ther. 18, 41-46 10.1111/j.1755-5949.2010.00231.x
29. Hare, D. J., Lei, P., Ayton, S., Roberts, B. R., Grimm, R., George, J. L., Bishop, D. P., Beavis, A. D., Donovan, S. J., McColl, G., Volitakis, I., Masters, C. L., Adlard, P. A., Cherny, R. A., Bush, A. I., Finkelstein, D. I., and Doble, P. A. (2014) An iron-dopamine index predicts risk of parkinsonian neurodegeneration in the substantia nigra pars compacta Chem. Sci. 5, 2160-2169 10.1039/C3SC53461H
30. Paul, B., Hare, D. J., Bishop, D. P., Paton, C., Nguyen, V. T., Cole, N., Niedwiecki, M. N., Andreozzi, E., Vais, A., Billings, J. L., Bray, L., Bush, A. I., McColl, G., Roberts, B. R., Adlard, P. A., Finkelstein, D. I., Hellstrom, J., Hergt, J. M., Woodhead, J., and Doble, P. A. (2015) Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging Chem. Sci. 6, 5383-5393 10.1039/C5SC02231B
31. Cahill, C. M., Lahiri, D. K., Huang, X., and Rogers, J. T. (2009) Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases Biochim. Biophys. Acta, Gen. Subj. 1790, 615-628 10.1016/j.bbagen.2008.12.001
32. Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H., and Del Tredici, K. (2004) Stages in the development of Parkinson's disease-related pathology Cell Tissue Res. 318, 121-134 10.1007/s00441-004-0956-9
33. Rodriguez-Oroz, M. C., Jahanshahi, M., Krack, P., Litvan, I., Macias, R., Bezard, E., and Obeso, J. A. (2009) Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms Lancet Neurol. 8, 1128-1139 10.1016/S1474-4422(09)70293-5
34. Aarsland, D., Zaccai, J., and Brayne, C. (2005) A systematic review of prevalence studies of dementia in Parkinson's disease Mov. Disord. 20, 1255-1263 10.1002/mds.20527
35. Buter, T. C., van den Hout, A., Matthews, F. E., Larsen, J. P., Brayne, C., and Aarsland, D. (2008) Dementia and survival in Parkinson disease: a 12-year population study Neurology 70, 1017-1022 10.1212/01.wnl.0000306632.43729.24
36. Hughes, T. A., Ross, H. F., Musa, S., Bhattacherjee, S., Nathan, R. N., Mindham, R. H., and Spokes, E. G. (2000) A 10-year study of the incidence of and factors predicting dementia in Parkinson's disease Neurology 54, 1596-1602 10.1212/WNL.54.8.1596
37. Puschmann, A., Ross, O. A., Vilarino-Guell, C., Lincoln, S. J., Kachergus, J. M., Cobb, S. A., Lindquist, S. G., Nielsen, J. E., Wszolek, Z. K., Farrer, M., Widner, H., van Westen, D., Hagerstrom, D., Markopoulou, K., Chase, B. A., Nilsson, K., Reimer, J., and Nilsson, C. (2009) A Swedish family with de novo alpha-synuclein A53T mutation: Evidence for early cortical dysfunction Parkinsonism Relat. Disord. 15, 627-632 10.1016/j.parkreldis.2009.06.007
38. Emre, M., Aarsland, D., Albanese, A., Byrne, E. J., Deuschl, G., De Deyn, P. P., Durif, F., Kulisevsky, J., van Laar, T., Lees, A., Poewe, W., Robillard, A., Rosa, M. M., Wolters, E., Quarg, P., Tekin, S., and Lane, R. (2004) Rivastigmine for dementia associated with Parkinson's disease N. Engl. J. Med. 351, 2509-2518 10.1056/NEJMoa041470
39. McKeith, I., Del Ser, T., Spano, P., Emre, M., Wesnes, K., Anand, R., Cicin-Sain, A., Ferrara, R., and Spiegel, R. (2000) Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study Lancet 356, 2031-2036 10.1016/S0140-6736(00)03399-7
40. Wesnes, K. A., McKeith, I. G., Ferrara, R., Emre, M., Del Ser, T., Spano, P. F., Cicin-Sain, A., Anand, R., and Spiegel, R. (2002) Effects of rivastigmine on cognitive function in dementia with lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system Dementia Geriatr. Cognit. Disord. 13, 183-192 10.1159/000048651
41. Moretti, D. V., Binetti, G., Zanetti, O., and Frisoni, G. B. (2014) Rotigotine is safe and efficacious in Atypical Parkinsonism Syndromes induced by both α-synucleinopathy and tauopathy Neuropsychiatr. Dis. Treat. 10, 1003-1009 10.2147/NDT.S64015
42. Devos, D., Moreau, C., Devedjian, J. C., Kluza, J., Petrault, M., Laloux, C., Jonneaux, A., Ryckewaert, G., Garcon, G., Rouaix, N., Duhamel, A., Jissendi, P., Dujardin, K., Auger, F., Ravasi, L., Hopes, L., Grolez, G., Firdaus, W., Sablonniere, B., Strubi-Vuillaume, I., Zahr, N., Destee, A., Corvol, J. C., Poltl, D., Leist, M., Rose, C., Defebvre, L., Marchetti, P., Cabantchik, Z. I., and Bordet, R. (2014) Targeting chelatable iron as a therapeutic modality in Parkinson's disease Antioxid. Redox Signaling 21, 195-210 10.1089/ars.2013.5593
43. Kaur, D. and Andersen, J. K. (2002) Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility? Aging Cell 1, 17-21 10.1046/j.1474-9728.2002.00001.x
44. Tõugu, V., Tiiman, A., and Palumaa, P. (2011) Interactions of Zn(II) and Cu(II) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity Metallomics 3, 250-261 10.1039/c0mt00073f
45. Feng, B. Y., Toyama, B. H., Wille, H., Colby, D. W., Collins, S. R., May, B. C. H., Prusiner, S. B., Weissman, J., and Shoichet, B. K. (2008) Small-molecule aggregates inhibit amyloid polymerization Nat. Chem. Biol. 4, 197-199 10.1038/nchembio.65
46. Ryan, T. M., Roberts, B. R., McColl, G., Hare, D. J., Doble, P. A., Li, Q.-X., Lind, M., Roberts, A. M., Mertens, H. D. T., Kirby, N., Pham, C. L. L., Hinds, M. G., Adlard, P. A., Barnham, K. J., Curtain, C. C., and Masters, C. L. (2015) Stabilization of nontoxic aβ-oligomers: insights into the mechanism of action of hydroxyquinolines in Alzheimer's disease J. Neurosci. 35, 2871-2884 10.1523/JNEUROSCI.2912-14.2015
47. Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., and Lee, V. M. (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein Neuron 34, 521-533 10.1016/S0896-6273(02)00682-7
48. Petroske, E., Meredith, G. E., Callen, S., Totterdell, S., and Lau, Y. S. (2001) Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment Neuroscience 106, 589-601 10.1016/S0306-4522(01)00295-0
49. Ikeda, M., Kawarabayashi, T., Harigaya, Y., Sasaki, A., Yamada, S., Matsubara, E., Murakami, T., Tanaka, Y., Kurata, T., Wuhua, X., Ueda, K., Kuribara, H., Ikarashi, Y., Nakazato, Y., Okamoto, K., Abe, K., and Shoji, M. (2009) Motor impairment and aberrant production of neurochemicals in human alpha-synuclein A30P+A53T transgenic mice with alpha-synuclein pathology Brain Res. 1250, 232-241 10.1016/j.brainres.2008.10.011
50. Avale, M. E., Faure, P., Pons, S., Robledo, P., Deltheil, T., David, D. J., Gardier, A. M., Maldonado, R., Granon, S., Changeux, J. P., and Maskos, U. (2008) Interplay of beta2∗ nicotinic receptors and dopamine pathways in the control of spontaneous locomotion Proc. Natl. Acad. Sci. U. S. A. 105, 15991-15996 10.1073/pnas.0807635105
51. Parish, C. L., Finkelstein, D. I., Drago, J., Borrelli, E., and Horne, M. K. (2001) The role of dopamine receptors in regulating the size of axonal arbors J. Neurosci. 21, 5147-5157
52. Parish, C. L., Finkelstein, D. I., Tripanichkul, W., Satoskar, A. R., Drago, J., and Horne, M. K. (2002) The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice J. Neurosci. 22, 8034-8041
53. Ayton, S., George, J. L., Adlard, P. A., Bush, A. I., Cherny, R. A., and Finkelstein, D. I. (2013) The effect of dopamine on MPTP-induced rotarod disability Neurosci. Lett. 543, 105-109 10.1016/j.neulet.2013.02.066
54. Lei, P., Ayton, S., Finkelstein, D. I., Spoerri, L., Ciccotosto, G. D., Wright, D. K., Wong, B. X., Adlard, P. A., Cherny, R. A., Lam, L. Q., Roberts, B. R., Volitakis, I., Egan, G. F., McLean, C. A., Cappai, R., Duce, J. A., and Bush, A. I. (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export Nat. Med. 18, 291-295 10.1038/nm.2613
55. Hung, L. W., Villemagne, V. L., Cheng, L., Sherratt, N. A., Ayton, S., White, A. R., Crouch, P. J., Lim, S., Leong, S. L., Wilkins, S., George, J., Roberts, B. R., Pham, C. L., Liu, X., Chiu, F. C., Shackleford, D. M., Powell, A. K., Masters, C. L., Bush, A. I., O'Keefe, G., Culvenor, J. G., Cappai, R., Cherny, R. A., Donnelly, P. S., Hill, A. F., Finkelstein, D. I., and Barnham, K. J. (2012) The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease J. Exp. Med. 209, 837-854 10.1084/jem.20112285
56. Oaks, A. W., Frankfurt, M., Finkelstein, D. I., and Sidhu, A. (2013) Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function PLoS One 8, e60378 10.1371/journal.pone.0060378
57. Li, Y., Kolb, B., and Robinson, T. E. (2003) The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen Neuropsychopharmacology 28, 1082-1085 10.1038/sj.npp.1300115
58. McNeill, T. H., Brown, S. A., Rafols, J. A., and Shoulson, I. (1988) Atrophy of medium spiny I striatal dendrites in advanced Parkinson's disease Brain Res. 455, 148-152 10.1016/0006-8993(88)90124-2
59. Adlard, P. A., Bica, L., White, A. R., Nurjono, M., Filiz, G., Crouch, P. J., Donnelly, P. S., Cappai, R., Finkelstein, D. I., and Bush, A. I. (2011) Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease PLoS One 6, e17669 10.1371/journal.pone.0017669
60. Adlard, P. A., Cherny, R. A., Finkelstein, D. I., Gautier, E., Robb, E., Cortes, M., Volitakis, I., Liu, X., Smith, J. P., Perez, K., Laughton, K., Li, Q. X., Charman, S. A., Nicolazzo, J. A., Wilkins, S., Deleva, K., Lynch, T., Kok, G., Ritchie, C. W., Tanzi, R. E., Cappai, R., Masters, C. L., Barnham, K. J., and Bush, A. I. (2008) Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta Neuron 59, 43-55 10.1016/j.neuron.2008.06.018
61. von Bohlen und Halbach, O., Zacher, C., Gass, P., and Unsicker, K. (2006) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice J. Neurosci. Res. 83, 525-531 10.1002/jnr.20759
62. Tsika, E., Moysidou, M., Guo, J., Cushman, M., Gannon, P., Sandaltzopoulos, R., Giasson, B. I., Krainc, D., Ischiropoulos, H., and Mazzulli, J. R. (2010) Distinct region-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration J. Neurosci. 30, 3409-3418 10.1523/JNEUROSCI.4977-09.2010
63. Zhou, J., Broe, M., Huang, Y., Anderson, J. P., Gai, W. P., Milward, E. A., Porritt, M., Howells, D., Hughes, A. J., Wang, X., and Halliday, G. M. (2011) Changes in the solubility and phosphorylation of alpha-synuclein over the course of Parkinson's disease Acta Neuropathol. 121, 695-704 10.1007/s00401-011-0815-1
64. Cappai, R., Leck, S. L., Tew, D. J., Williamson, N. A., Smith, D. P., Galatis, D., Sharples, R. A., Curtain, C. C., Ali, F. E., Cherny, R. A., Culvenor, J. G., Bottomley, S. P., Masters, C. L., Barnham, K. J., and Hill, A. F. (2005) Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway FASEB J. 19, 1377-1379 10.1096/fj.04-3437fje
65. Raman, B., Ban, T., Yamaguchi, K.-i., Sakai, M., Kawai, T., Naiki, H., and Goto, Y. (2005) Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid {beta} peptide J. Biol. Chem. 280, 16157-16162 10.1074/jbc.M500309200
66. Fleming, S. M., Fernagut, P.-O., and Chesselet, M.-F. (2005) Genetic mouse models of parkinsonism: Strengths and limitations NeuroRx 2, 495-503 10.1602/neurorx.2.3.495
67. Hare, D. J., Adlard, P. A., Doble, P. A., and Finkelstein, D. I. (2013) Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity Metallomics 5, 91-109 10.1039/c2mt20164j
68. Bezard, E., Yue, Z., Kirik, D., and Spillantini, M. G. (2013) Animal models of Parkinson's disease: Limits and relevance to neuroprotection studies Mov. Disord. 28, 61-70 10.1002/mds.25108
69. Mattila, P. M., Rinne, J. O., Helenius, H., Dickson, D. W., Roytta, M., and Matilla, P. M. (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease Acta Neuropathol. 100, 285-290 10.1007/s004019900168
70. Hurtig, H. I., Trojanowski, J. Q., Galvin, J., Ewbank, D., Schmidt, M. L., Lee, V. M., Clark, C. M., Glosser, G., Stern, M. B., Gollomp, S. M., and Arnold, S. E. (2000) Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease Neurology 54, 1916-1921 10.1212/WNL.54.10.1916
71. Farrer, M., Chan, P., Chen, R., Tan, L., Lincoln, S., Hernandez, D., Forno, L., Gwinn Hardy, K., Petrucelli, L., Hussey, J., Singleton, A., Tanner, C., Hardy, J., and Langston, J. W. (2001) Lewy bodies and parkinsonism in families with parkin mutations Ann. Neurol. 50, 293-300 10.1002/ana.1132
72. Goldberg, M. S. and Lansbury, P. T., Jr. (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nat. Cell Biol. 2, E115-E119 10.1038/35017124
73. Terry, R. D. (2000) Do neuronal inclusions kill the cell? J. Neural. Transm. Suppl. 59, 91-93 10.1007/978-3-7091-6781-6-12
74. Gomez-Isla, T., Irizarry, M. C., Mariash, A., Cheung, B., Soto, O., Schrump, S., Sondel, J., Kotilinek, L., Day, J., Schwarzschild, M. A., Cha, J. H., Newell, K., Miller, D. W., Ueda, K., Young, A. B., Hyman, B. T., and Ashe, K. H. (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice Neurobiol. Aging 24, 245-258 10.1016/S0197-4580(02)00091-X
75. Freichel, C., Neumann, M., Ballard, T., Muller, V., Woolley, M., Ozmen, L., Borroni, E., Kretzschmar, H. A., Haass, C., Spooren, W., and Kahle, P. J. (2007) Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice Neurobiol. Aging 28, 1421-1435 10.1016/j.neurobiolaging.2006.06.013
76. Maskri, L., Zhu, X., Fritzen, S., Kuhn, K., Ullmer, C., Engels, P., Andriske, M., Stichel, C. C., and Lubbert, H. (2004) Influence of different promoters on the expression pattern of mutated human alpha-synuclein in transgenic mice Neurodegener. Dis. 1, 255-265 10.1159/000085064
77. Fearnley, J. M. and Lees, A. J. (1991) Aging and Parkinson's Disease: Substantia Nigra regional selectivity Brain 114, 2283-2301 10.1093/brain/114.5.2283
78. Morrish, P. K., Rakshi, J. S., Bailey, D. L., Sawle, G. V., and Brooks, D. J. (1998) Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [F-18] dopa PET J. Neurol., Neurosurg. Psychiatry 64, 314-319 10.1136/jnnp.64.3.314
79. Kordower, J. H., Olanow, C. W., Dodiya, H. B., Chu, Y., Beach, T. G., Adler, C. H., Halliday, G. M., and Bartus, R. T. (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson's disease Brain 136, 2419-2431 10.1093/brain/awt192
80. Lees, A. J. (1992) When did Ray Kennedy's Parkinson's disease begin? Mov. Disord. 7, 110-116 10.1002/mds.870070203
81. Zaja-Milatovic, S., Milatovic, D., Schantz, A. M., Zhang, J., Montine, K. S., Samii, A., Deutch, A. Y., and Montine, T. J. (2005) Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease Neurology 64, 545-547 10.1212/01.WNL.0000150591.33787.A4
82. Stanic, D., Parish, C. L., Zhu, W. M., Krstew, E. V., Lawrence, A. J., Drago, J., Finkelstein, D. I., and Horne, M. K. (2003) Changes in function and ultrastructure of striatal dopaminergic terminals that regenerate following partial lesions of the SNpc J. Neurochem. 86, 329-343 10.1046/j.1471-4159.2003.01843.x
83. Thomas, M. J., Beurrier, C., Bonci, A., and Malenka, R. C. (2001) Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine Nat. Neurosci. 4, 1217-1223 10.1038/nn757
84. Adlard, P. A., Parncutt, J. M., Finkelstein, D. I., and Bush, A. I. (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? J. Neurosci. 30, 1631-1636 10.1523/JNEUROSCI.5255-09.2010
85. Fredriksson, A., Schroder, N., Eriksson, P., Izquierdo, I., and Archer, T. (1999) Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice Toxicol. Appl. Pharmacol. 159, 25-30 10.1006/taap.1999.8711
86. Lhermitte, J., Kraus, W. M., and McAlpine, D. (1924) On the occurrence of abnormal deposits of iron in the brain in Parkinsonism with special reference to its location J. Neurol., Neurosurg. Psychiatry s1-5, 195-208 10.1136/jnnp.s1-5.19.195
87. Moos, T., Nielsen, T. R., Skjorringe, T., and Morgan, E. H. (2007) Iron trafficking inside the brain J. Neurochem. 103, 1730-1740 10.1111/j.1471-4159.2007.04976.x
88. Barnham, K. J., Haeffner, F., Ciccotosto, G. D., Curtain, C. C., Tew, D., Mavros, C., Beyreuther, K., Carrington, D., Masters, C. L., Cherny, R. A., Cappai, R., and Bush, A. I. (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid FASEB J. 18, 1427-1429 10.1096/fj.04-1890fje
89. Pezzella, A., d'Ischia, M., Napolitano, A., Misuraca, G., and Prota, G. (1997) Iron-mediated generation of the neurotoxin 6-hydroxydopamine quinone by reaction of fatty acid hydroperoxides with dopamine: a possible contributory mechanism for neuronal degeneration in Parkinson's disease J. Med. Chem. 40, 2211-2216 10.1021/jm970099t
90. Hong, L. and Simon, J. D. (2009) Binding of Cu(II) to human alpha-synucleins: comparison of wild type and the point mutations associated with the familial Parkinson's disease J. Phys. Chem. B 113, 9551-9561 10.1021/jp809773y
91. Bharathi and Rao, K. S. (2007) Thermodynamics imprinting reveals differential binding of metals to alpha-synuclein: relevance to Parkinson's disease Biochem. Biophys. Res. Commun. 359, 115-120 10.1016/j.bbrc.2007.05.060
92. Binolfi, A., Rasia, R. M., Bertoncini, C. W., Ceolin, M., Zweckstetter, M., Griesinger, C., Jovin, T. M., and Fernandez, C. O. (2006) Interaction of alpha-synuclein with divalent metal ions reveals key differences: A link between structure, binding specificity and fibrillation enhancement J. Am. Chem. Soc. 128, 9893-9901 10.1021/ja0618649
93. Golts, N., Snyder, H., Frasier, M., Theisler, C., Choi, P., and Wolozin, B. (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein J. Biol. Chem. 277, 16116-16123 10.1074/jbc.M107866200
94. Friedlich, A. L., Tanzi, R. E., and Rogers, J. T. (2007) The 5′-untranslated region of Parkinson's disease alpha-synuclein messengerRNA contains a predicted iron responsive element Mol. Psychiatry 12, 222-223 10.1038/sj.mp.4001937
95. Bandyopadhyay, S., Huang, X., Cho, H., Greig, N. H., Youdim, M. B., and Rogers, J. T. (2006) Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5′untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator J. Neural. Transm. Suppl. 71, 237-247 10.1007/978-3-211-33328-0-25
96. Di Vaira, M., Bazzicalupi, C., Orioli, P., and Messori, L. (2004) Clioquinol, a drug for Alzheimer's disease specifically interfering with brain metal metabolism: structural characterization of its zinc (II) and copper (II) complexes Inorg. Chem. 43, 3795-3797 10.1021/ic0494051
97. Kaur, D., Yantiri, F., Rajagopalan, S., Kumar, J., Mo, J. Q., Boonplueang, R., Viswanath, V., Jacobs, R., Yang, L., Beal, M. F., DiMonte, D., Volitaskis, I., Ellerby, L., Cherny, R. A., Bush, A. I., and Andersen, J. K. (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease Neuron 37, 899-909 10.1016/S0896-6273(03)00126-0
98. George, S., Mok, S. S., Nurjono, M., Ayton, S., Finkelstein, D. I., Masters, C. L., Li, Q.-X., and Culvenor, J. G. (2010) α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment J. Mol. Neurosci. 42, 243-254 10.1007/s12031-010-9378-1
99. Crouch, P. J., Hung, L. W., Adlard, P. A., Cortes, M., Lal, V., Filiz, G., Perez, K. A., Nurjono, M., Caragounis, A., Du, T., Laughton, K., Volitakis, I., Bush, A. I., Li, Q. X., Masters, C. L., Cappai, R., Cherny, R. A., Donnelly, P. S., White, A. R., and Barnham, K. J. (2009) Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation Proc. Natl. Acad. Sci. U. S. A. 106, 381-386 10.1073/pnas.0809057106
100. Bevins, R. A. and Besheer, J. (2006) Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory' Nat. Protoc. 1, 1306-1311 10.1038/nprot.2006.205