Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Visanji, Naomi P.; Collingwood, Joanna F.; Finnegan, Mary E.; Tandon, Anurag; House, Emily; Hazrati, Lili-Naz
Publisher: IOS Press
Languages: English
Types: Article
Subjects: RC0321

Classified by OpenAIRE into

mesheuropmc: nervous system, nervous system diseases
Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • [1] Forno LS (1996) Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol, 55, 259-272.
    • [2] Crichton R & Ward RJ (2008) Metal-based neurodegeneration - from molecular mechanisms to therapeutic strategies in Parkinson's disease. John Wiley & Sons Ltd, 2006.
    • [3] Davies P, Moualla D & Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One, 6, e15814.
    • [4] Ayton S, Lei P, Bush AI & Finkelstein DI (2013) Alpha synuclein is a major regulator of iron homeostasis, in 11th Annual Conference on Alzheimer's and Parkinson's diseases (AD/PD). Florence, 2013.
    • [5] Riederer P, Dirr A, Goetz M, Sofic E, Jellinger K & Youdim MB (1992) Distribution of iron in different brain regions and subcellular compartments in Parkinson's disease. Ann Neurol, 32 (Suppl) S101-s104.
    • [6] Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR & Daniel SE, et al. (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain, 114(Pt 4), 1953-1975.
    • [7] Dexter DT, Jenner P, Schapira AH & Marsden CD (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group. Ann Neurol, 32(Suppl), S94-S100.
    • [8] Friedman A, Arosio P, Finazzi D, Koziorowski D & GalazkaFriedman J (2011) Ferritin as an important player in neurodegeneration. Parkinsonism Relat Disord, 17, 423-430.
    • [9] Arosio P & Levi S (2010) Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta, 1800, 783-792.
    • [10] Bolzoni F, Giraudo S, Lopiano L, Bergamasco B, Fasano M & Crippa PR (2002) Magnetic investigations of human mesencephalic neuromelanin. Biochim Biophys Acta, 1586, 210-218.
    • [11] Hautot D, Pankhurst QA & Dobson J (2005) Superconducting quantum interference device measurements of dilute magnetic materials in biological samples. Rev Sci Instrum, 76.
    • [12] Collingwood JF, Chong RK, Kasama T, Cervera-Gontard L, Dunin-Borkowski RE & Perry G, et al. (2008) Threedimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material. J Alzheimers Dis, 14, 235-245.
    • [13] Hautot D, Pankhurst QA & Dobson J (2005) Superconducting quantum interference device measurements of dilute magnetic materials in biological samples. Rev Sci Instrum, 76.
    • [14] House E, Esiri M, Forster G, Ince PG & Exley C (2012) Aluminium, iron and copper in human brain tissues donated to the Medical Research Council's Cognitive Function and Ageing Study. Metallomics, 4, 56-65.
    • [15] Zecca L, Gallorini M, Schunemann V, Trautwein AX, Gerlach M & Riederer P, et al. (2001) Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: Consequences for iron storage and neurodegenerative processes. J Neurochem, 76, 1766-1773.
    • [16] Crichton RR, Dexter DT & Ward RJ (2011) Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm, 118, 301-314.
    • [17] Friedman A, Galazka-Friedman J & Koziorowski D (2009) Iron as a cause of Parkinson disease - a myth or a well established hypothesis? Parkinsonism Relat Disord, 15(Suppl 3), S212-S214.
    • [18] Earle KM (1968) Studies on Parkinson's disease including x-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol, 27, 1-14.
    • [19] Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP & Hebenstreit G, et al. (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm, 74, 199-205.
    • [20] Griffiths PD & Crossman AR (1993) Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson's disease and Alzheimer's disease. Dementia, 4, 61-65.
    • [21] Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR & Edwardson JA, et al. (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology, 68, 1820-1825.
    • [22] De Volder AG, Francart J, Laterre C, Dooms G, Bol A & Michel C et al. (1989) Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration. Ann Neurol, 26, 239-247.
    • [23] Mash DC, Pablo J, Buck BE, Sanchez-Ramos J & Weiner WJ (1991) Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice. Exp Neurol, 114, 73-81.
    • [24] Block ML, Zecca L & Hong JS (2007) Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat Rev Neurosci, 8, 57-69.
    • [25] McGeer PL, Itagaki S, Boyes BE & McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology, 38, 1285-1291.
    • [26] Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA & Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol, 46, 598-605.
    • [27] Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M & Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol, 106, 518-526.
    • [28] Moos T, Rosengren Nielsen T, Skjorringe T & Morgan EH (2007) Iron trafficking inside the brain. J Neurochem, 103, 1730-1740.
    • [29] Persichini T, De Francesco G, Capone C, Cutone A, di Patti MC & Colasanti M, et al. (2012) Reactive oxygen [31] [33] species are involved in ferroportin degradation induced by ceruloplasmin mutant Arg701Trp. Neurochem Int, 60, 360- 364.
    • Moos T & Rosengren Nielsen T (2006) Ferroportin in the postnatal rat brain: Implications for axonal transport and neuronal export of iron. Semin Pediatr Neurol, 13, 149-157.
    • De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E & Sundquist WI, et al. (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell, 18, 2569-2578.
    • Rouault TA (2001) Systemic iron metabolism: A review and implications for brain iron metabolism. Pediatr Neurol, 25, 130-137.
    • Kono S, Yoshida K, Tomosugi N, Terada T, Hamaya Y & Kanaoka S, et al. (2010) Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin.
    • Biochim Biophys Acta, 1802, 968-975.
    • Yomono H, Kurisaki H, Murayama S, Hebisawa A, Miyajima H & Takahashi Y (2003) An autopsy case of multiple system atrophy with a heteroallelic ceruloplasmin gene mutation.
    • Rinsho Shinkeigaku, 43, 398-402.
    • [35] Kurisaki H, Yomono H, Murayama S & Hebisawa A (2002) Multiple system atrophy with a-/hypo-ceruloplasminemia: Distribution of iron in brains of 2 autopsy cases. Rinsho Shinkeigaku, 42, 293-298.
    • [36] Cairo G, Tacchini L & Pietrangelo A (1998) Lack of coordinate control of ferritin and transferrin receptor expression during rat liver regeneration. Hepatology, 28, 173-178.
    • [37] Zechel S, Huber-Wittmer K & von Bohlen und Halbach O (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res, 84, 790-800.
    • [38] Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A & Ward DM, et al. (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 306, 2090-2093.
    • [39] Weiss G & Goodnough LT (2005) Anemia of chronic disease. N Engl J Med, 352, 1011-1023.
    • [40] Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T & Hirose T (2004) Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol, 63, 43-52.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article