Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease.
Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most extensive in the subpopulation of melanized neurones located in the substantia nigra pars compacta. Iron accumulation, together with a lack of up-regulation of the iron-storing protein, ferritin, has been reported and may contribute to increased oxidative stress in this region. We investigated the binding activity of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes ferritin mRNA translation, in the substantia nigra of a group of parkinsonian patients who presented a statistically significant reduction in the number of nigral melanized-neurones and an increased iron content, together with unchanged H-ferritin and L-ferritin subunit levels as compared to matched controls. The levels of ferritin mRNAs and the binding activity of IRP1 to the iron-responsive element of ferritin mRNA did not differ significantly between the two groups. Moreover, there was no detectable contribution of the iron regulatory protein-2 (IRP2) binding activity. No change in IRP1 control of ferritin mRNA translation explains the lack of up-regulation of ferritin expression in cytoplasmic extracts of SNpc that would be normally expected with cytosolic iron accumulation. The data of this study do not favor changes in transcription and post-transcriptional regulation of ferritin expression in Parkinson's disease and suggest a 'compartmentalized' iron accumulation.
Faucheux
Baptiste A
BA
INSERM, U289 and U360 et Centre de Recherches de Neurologie Neuropathologie de l'Association Claude Bernard, Hôpital de la Salpêtrière, Paris, France. baptiste.faucheux@hups.jussieu.fr
Martin
Marie-Elise
ME
Beaumont
Carole
C
Hunot
Stéphane
S
Hauw
Jean-Jacques
JJ
Agid
Yves
Y
Hirsch
Etienne C
EC
D000368:Aged; D000369:Aged, 80 and over; D002452:Cell Count; D003593:Cytoplasm / Q000737:chemistry; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005293:Ferritins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000032:analysis; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D015203:Reproducibility of Results; D013378:Substantia Nigra / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D021122:Protein Subunits; D012333:RNA, Messenger; D005293:Ferritins; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2