Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine

نویسندگان

  • Jianfang Chen
  • Eileen Marks
  • Barry Lai
  • Zhaojie Zhang
  • James A. Duce
  • Linh Q. Lam
  • Irene Volitakis
  • Ashley I. Bush
  • Steven Hersch
  • Jonathan H. Fox
چکیده

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Short-term Chelating Efficacy of Deferoxamine in Iron Overloaded Rat Hepatocytes

Abstract Background: Iron overload is a clinical consequence of repeated blood transfusions and causes significant organ damage, morbidity, and mortality in the absence of proper treatment. The primary targets of Iron chelators used for treating transfusional Iron overload are the prevention of Iron ingress into tissues and its intracellular scavenging. The present study was aimed at elucid...

متن کامل

Comparison of Deferoxamine, Activated Charcoal, and Vitamin C in ‎Changing the Serum Level of Fe in Iron Overloaded Rats

Background: Iron is an essential mineral for normal cellular physiology but its ‎overload can lead to cell injury. For many years, deferoxamine injection has been used ‎as an iron chelator for treatment of iron overload. The aim of this study is to compare ‎oral deferoxamine, activated charcoal, and vitamin C, as an absorbent factor of Fe, in ‎changing the serum level of iron in iron overload r...

متن کامل

Ferric iron chelation lowers brain iron levels after intracerebral hemorrhage in rats but does not improve outcome.

Iron-mediated free radical damage contributes to secondary damage after intracerebral hemorrhage (ICH). Iron is released from heme after hemoglobin breakdown and accumulates in the parenchyma over days and then persists in the brain for months (e.g., hemosiderin). This non-heme iron has been linked to cerebral edema and cell death. Deferoxamine, a ferric iron chelator, has been shown to mitigat...

متن کامل

Sequential Deferoxamine - Deferasirox in Treatment of Major Thalassemia with Iron Overload

Abstract Background Iron overload is a major problem in patients with major thalassemia. An effective and safe iron chelator protocol with high compliance rate plays an important role in treatment of these patients. This study was done to assess the efficacy and safety of the sequential deferoxamine and deferasirox protocol in major thalassemia patients in Khuzestan province, Iran. Material ...

متن کامل

NUB1: enhancing clearance to decrease mutant huntingtin - HDBuzz - Huntington’s disease research news

Getting to the NUB of the matter Everyone has two copies of the huntingtin gene (the recipe for the huntingtin protein, if you like). Patients with Huntington’s disease (HD), however, have one extra-long copy of the huntingtin gene, caused by a mutation, or misspelling in the genetic code. This means that in addition to the normal version of the huntingtin protein, HD patients also produce its ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2013