Multiple studies implicate iron in the pathophysiology of Parkinson’s disease (PD). In the brains of patients with PD, iron levels are elevated and the levels of iron-binding proteins are abnormal. Iron has been suspected to contribute to PD because Fe(II) is known to promote oxidative damage. Recent studies suggest that an additional mechanism by which iron might contribute to PD is by inducing aggregation of the α-synuclein, which is a protein that accumulates in Lewy bodies in PD.
Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, and others. 2000. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron25:239.
2.
Barbiroli B, Martinelli P, Patuelli A, Lodi R, Iotti S, Cortelli P, and others. 1999. Phosphorus magnetic resonance spectroscopy in multiple system atrophy and Parkinson’s disease. Mov Disord14:430.
3.
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci3:1301.
4.
Chen X, Xia Y, Alford M, DeTeresa R, Hansen L, Klauber MR, and others. 1995. The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer’s disease. Ann Neurol38:653.
5.
Choi P, Golts N, Snyder H, Petrucelli L, Chong M, Hardy J, and others. 2001. Co-association of parkin and α-synuclein. Submitted.
6.
Choi P, Ostrerova-Golts N, Sparkman D, Cochran E, Lee J, Wolozin B. 2000. Parkin is metabolized by the ubiquitin/proteosomal system. Neuroreport11:2635.
7.
Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P. 1995. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer’s diseased brains. J Neurochem65:717.
8.
Conway K, Harper J, Lansbury P. 1998. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nature Med4:1318.
9.
Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, and others. 1997. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell90:537.
10.
Dickson D, Lin W-l, Liu W, Yen S. 1999. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol9:721.
11.
Engelender S, Kaminsky Z, Guo X, Sharp A, Amaravi R, Kleiderlein J, and others. 1999. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet22:110.
12.
Faucheux BA, Herrero MT, Villares J, Levy R, Javoy-Agid F, Obeso JA, and others. 1995. Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson’s disease and MPTP-lesioned monkeys. Brain Res691:115.
13.
Faucheux BA, Nillesse N, Damier P, Spik G, Mouatt-Prigent A, Pierce A, and others. 1995. Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. Proc Natl Acad Sci U S A92:9603.
14.
Feany MB, Bender WW. 2000. A Drosophila model of Parkinson’s disease. Nature404:394.
15.
Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ. 2000. Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol157:361.
16.
Ghee M, Fournier A, Mallet J. 2000. Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex. J Neurochem75:2221.
17.
Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, and others. 2000. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science290:985.
18.
Giasson BI, Murray II, Trojanowski JQ, Lee VM. 2000. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem276:2380-2386.
19.
Golts N, Snyder H, Frasier M, Choi P, Wolozin B. 2001. Inhibition of α-synuclein aggregation by magnesium. Submitted.
20.
Grau AJ, Willig V, Fogel W, Werle E. 2001. Assessment of plasma lactoferrin in Parkinson’s disease. Mov Disord16:131.
21.
Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, and others. 1999. Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport10:717.
22.
Hashimoto M, Takeda A, Hsu L, Takenouchi T, Masliah E. 1999. Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J Biol Chem274:28849.
23.
Hirsch EC, Graybiel AM, Agid Y. 1989. Selective vulnerability of pigmented dopaminergic neurons in Parkinson’s disease. Acta Neurol Scand Suppl126:19.
24.
Hunot S, Brugg B, Ricard D, Michel P, Muriel M, Ruberg M, and others. 1997. Nuclear translocation of NF-k B is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci U S A94:7531.
25.
Jarrett J, Berger E, Lansbury P. 1993. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry32:4693.
26.
Jenco J, Rawlingson A, Daniels B, Morris A. 1998. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by α and β synucleins. Biochemistry37:4901.
27.
Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, and others. 1999. Alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem274:25481.
28.
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, and others. 1998. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet18:106.
29.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, and others. 1998. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A95:6448.
30.
Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, and others. 2000. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet25:402.
31.
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, and others. 1997. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology48:1583.
32.
Logroscino G, Marder K, Graziano J, Freyer G, Slavkovich V, LoIacono N, and others. 1997. Altered systemic iron metabolism in Parkinson’s disease. Neurology49:714.
33.
Martin W, Roberts T, Ye F, Allen P. 1998. Increased basal ganglia iron in striatonigral degeneration: in vivo estimation with magnetic resonance. Can J Neurol Sci25:44.
34.
McNaught KS, Jenner P. 2001. Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett297:191.
35.
Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. 2000. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci20:3214.
36.
Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, and others. 1999. Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett447:195.
37.
Nakamura K, Wang W, Kang U. 1997. The role of glutathione in dopaminergic neuronal survival. J Neurochem69:1850.
38.
Newell KL, Boyer P, Gomez-Tortosa E, Hobbs W, Hedley-Whyte ET, Vonsattel JP, and others. 1999. Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury. J Neuropathol Exp Neurol58:1263.
39.
Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, and others. 2001. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science291:2423.
40.
Ostrerova N, Petrucelli L, Farrer M, Mehta N, Alexander P, Choi P, and others. 1999. α-synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci19:5782.
41.
Ostrerova-Golts N, Petrucelli L, Hardy J, Lee J, Farrer M, Wolozin B. 2000. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci20:6048.
42.
Perry T, Godin D, Hansen S. 1982. Parkinson’s disease: a disorder due to nigral glutathione deficiency. Neurosci Lett33:305.
43.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, and others. 1997. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science276:2045.
44.
Ponka P, Beaumont C, Richardson D. 1998. Function and regulation of transferrin and ferritin. Semin Hematol35:35.
45.
Price DL, Wong PC, Markowska AL, Lee MK, Thinakaren G, Cleveland DW, and others. 2000. The value of transgenic models for the study of neurodegenerative diseases. Ann N Y Acad Sci920:179.
46.
Pronin AN, Morris AJ, Surguchov A, Benovic JL. 2000. Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem275:26515-26522.
47.
Rybicki BA, Johnson CC, Uman J, Gorell JM. 1993. Parkinson’s disease mortality and the industrial use of heavy metals in Michigan. Mov Disord8:87.
48.
Saudou F, Finkbeiner S, Devys D, Greenberg M. 1998. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with formation of intranuclear inclusions. Cell95:55.
49.
Semchuk KM, Love EJ, Lee RG. 1991. Parkinson’s disease and exposure to rural environmental factors: a population based case-control study. Can J Neurol Sci18:279.
50.
Soto C, Sigurdsson E, Morelli L, Kumar R, Castano E, Frangione B. 1998. Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nature Med4:822.
51.
Spillantini M, Schmidt M, Lee VM, Trojanowski J, Jakes R, Goedert M. 1997. α-synuclein in Lewy bodies. Nature388:839.
52.
Thomson AM, Rogers JT, Leedman PJ. 1999. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol31:1139.
53.
Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross CA, Takahashi H. 2000. Synphilin-1 is present in Lewy bodies in Parkinson’s disease. Ann Neurol47:521.
54.
Wolozin B, Behl C. 2000. Mechanisms of neurodegenerative disorders. Part 1: protein aggregates. Arch Neurol57:793.
55.
Wood S, Wypych J, Steavenson S, Louis J, Citron M, Biere A. 1999. α-synuclein fibrillogenesis is nucleation-dependent: implications for Parkinson’s disease. J Biol Chem274:19509.
56.
Zecca L, Gallorini M, Schunemann V, Trautwein AX, Gerlach M, Riederer P, and others. 2001. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem76:1766.