Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease

GLIA - Tập 55 Số 10 - Trang 1074-1084 - 2007
Danielle A. Simmons1,2, Malcolm Casale1,2, Betzi Alcon2, Nha Pham1, Natasha Narayan1, Gary Lynch1
1Department of Psychiatry and Human Behavior, University of California, Irvine, California
2Thuris Corporation, Irvine, California

Tóm tắt

AbstractHuntington's Disease (HD) is characterized primarily by neuropathological changes in the striatum, including loss of medium‐spiny neurons, nuclear inclusions of the huntingtin protein, gliosis, and abnormally high iron levels. Information about how these conditions interact, or about the temporal order in which they appear, is lacking. This study investigated if, and when, iron‐related changes occur in the R6/2 transgenic mouse model of HD and compared the results with those from HD patients. Relative to wild‐type mice, R6/2 mice had increased immunostaining for ferritin, an iron storage protein, in the striatum beginning at 2–4 weeks postnatal and in cortex and hippocampus starting at 5–7 weeks. The ferritin staining was found primarily in microglia, and became more pronounced as the mice matured. Ferritin‐labeled microglia in R6/2 mice appeared dystrophic in that they had thick, twisted processes with cytoplasmic breaks; some of these cells also contained the mutant huntingtin protein. Brains from HD patients (Vonsattel grades 0–4) also had increased numbers of ferritin‐containing microglia, some of which were dystrophic. The cells were positive for Perl's stain, indicating that they contained abnormally high levels of iron. These results provide the first evidence that perturbations to iron metabolism in HD are predominately associated with microglia and occur early enough to be important contributors to HD progression. © 2007 Wiley‐Liss, Inc.

Từ khóa


Tài liệu tham khảo

10.1016/S1367-5931(99)80033-7

Allen W, 1997, Rho,Rac and Cdc42 regulate actin organization and cell adhesion in macrophages, J Cell Sci, 110, 707, 10.1242/jcs.110.6.707

10.1073/pnas.84.23.8478

10.1016/S0730-725X(96)00234-2

10.1001/archneur.56.5.569

Bartzokis G, 1994, In vivo MR evaluation of age‐related increases in brain iron, AJNR Am J Neuroradiol, 15, 1129

Bartzokis G, 2000, MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease, Cell Mol Biol (Noisy‐le‐grand), 46, 821

10.1016/j.neurobiolaging.2006.02.005

10.1196/annals.1306.019

10.1016/S0005-2728(98)00114-5

10.1146/annurev.nutr.23.020102.075739

10.1080/1029842021000045444

10.1046/j.1471-4159.2001.00608.x

10.1097/01.rmr.0000245461.90406.ad

10.1016/0304-3940(91)90711-2

10.1007/s00018-006-6242-0

10.1002/ana.410410514

10.1111/j.1750-3639.1999.tb00216.x

10.1523/JNEUROSCI.19-08-03248.1999

10.1126/science.2452485

10.1038/nrn1806

10.1002/(SICI)1096-9861(19981012)400:1<73::AID-CNE5>3.0.CO;2-Q

Chen J, 1993, MR of human postmortem brain tissue: Correlative study between T2 and assays of iron and ferritin in Parkinson and Huntington disease, AJNR Am J Neuroradiol, 14, 275

10.1002/ana.410320710

10.1002/jnr.490310111

10.1002/jnr.490370405

10.1007/0-387-23226-5_12

10.1016/S0092-8674(00)80513-9

10.1002/ana.410320716

10.1016/0003-9861(91)90366-Q

10.1046/j.1471-4159.1998.70062492.x

10.1006/exnr.1997.6724

10.1111/j.1742-4658.2006.05537.x

10.1016/S0306-4522(96)00607-0

Group HsDCR, 1993, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes, Cell, 72, 971, 10.1016/0092-8674(93)90585-E

10.1007/BF00334497

10.1016/j.nbd.2006.02.011

10.1016/j.expneurol.2005.01.013

10.1126/science.280.5372.2074

10.1016/0003-9861(86)90305-X

10.1016/S0169-328X(99)00011-X

10.1016/S0304-3940(02)00888-1

10.1073/pnas.93.16.8175

10.1093/hmg/9.19.2789

Hoffman K, 1991, Ascorbic acid and iron metabolism: Alterations in lysosomal function, Am J Clin Nutr, 54, 11885, 10.1093/ajcn/54.6.1188s

10.1016/j.brainresrev.2004.04.007

10.1007/s11064-006-9101-3

10.1006/bbrc.1996.1112

10.1016/S0169-328X(98)00040-0

10.1007/BF02252926

10.1002/ana.10483

10.1074/jbc.M109218200

10.1007/BF00294369

10.1016/S1383-5742(97)00035-5

Kaur C, 1995, Transient expression of transferrin receptors and localisation of iron in amoeboid microglia in postnatal rats, J Anat, 186, 165

10.1016/j.arr.2004.01.003

10.1523/JNEUROSCI.20-19-07268.2000

10.1002/jnr.20562

Klintworth GK, 1973, Advances in Neurology: Huntington's Chorea, 1872–1972

10.1002/ana.410410206

10.1007/BF00294257

10.1016/S0098-2997(00)00006-6

10.1523/JNEUROSCI.4283-04.2005

10.1002/glia.10261

10.1016/S0092-8674(00)81369-0

10.1016/j.jchromb.2005.04.023

10.1002/cne.10295

10.1016/j.freeradbiomed.2004.10.025

10.1007/BF02943258

10.1097/00005072-199111000-00005

10.1002/glia.1108

10.1073/pnas.0502177102

10.3233/JAD-2005-8211

10.1212/01.wnl.0000222734.56412.17

10.1016/0006-291X(85)91639-0

10.1016/j.jneuroim.2005.11.005

10.1046/j.1523-1755.1999.055Suppl.69002.x

10.1016/0092-8674(92)90164-8

10.1093/jnen/60.2.161

10.1016/0896-6273(95)90345-3

10.1136/oem.60.5.315

10.1083/jcb.200508072

10.1002/glia.10319

10.1016/j.tins.2006.07.001

10.1016/S0301-0082(98)00069-0

10.1038/ng1193-259

10.1007/BF00988605

10.1016/j.brainresbull.2006.10.029

10.1073/pnas.110078997

10.1074/jbc.M105343200

10.1177/1073858405280639

10.1097/00005072-198511000-00003

Wierzba‐Bobrowicz T, 2004, Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics, Folia Neuropathol, 42, 157

10.1016/0304-3940(95)11490-N

10.1097/00001756-199806220-00003

Young A, 1997, Impairment of energy metabolism and excitotoxic cell death in Huntington disease, Rev Neurol (Paris), 153, 496

10.1046/j.1471-4159.2003.01980.x

10.1126/science.1059581

Thông tin
Thông tin xuất bản

GLIA

Tập 55 Số 10

1074-1084

Thông tin tác giả