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The Journal of Neuroscience, January 2, 2008, 28(1):60-67; doi:10.1523/JNEUROSCI.3962-07.2008
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Neurobiology of Disease
Expression of a Mutant Form of the Ferritin Light Chain Gene Induces Neurodegeneration and Iron Overload in Transgenic Mice
Ruben Vidal,1 Leticia Miravalle,1 Xiaoying Gao,1 Ana G. Barbeito,1 Martin A. Baraibar,1 Shahryar K. Hekmatyar,2 Mario Widel,3 Navin Bansal,2 Marie B. Delisle,4 andBernardino Ghetti1 1Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, and 2Imaging Science Division, Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, 3Global Statistical Sciences, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, and 4Service d'Anatomie et de Cytologie Pathologiques, Hopitaux de Toulouse, 50032-31059 Toulouse, Cedex 4, France
Correspondence should be addressed to Dr. Ruben Vidal, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MSB A136, Indianapolis, IN 46202. Email: rvidal{at}iupui.edu
Increased iron levels and iron-mediated oxidative stress play an important role in the pathogenesis of many neurodegenerative diseases. The finding that mutations in the ferritin light polypeptide (FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy (HF) provided a direct connection between abnormal brain iron storage and neurodegeneration. HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic ferritin inclusion bodies in glia and neurons throughout the CNS and in tissues of multiple organ systems. Here we report that the expression in transgenic mice of a human FTL cDNA carrying a thymidine and cytidine insertion at position 498 (FTL498–499InsTC) leads to the formation of nuclear and cytoplasmic ferritin inclusion bodies. As in HF, ferritin inclusions are seen in glia and neurons throughout the CNS as well as in cells of other organ systems. Our studies show histological, immunohistochemical, and biochemical similarities between ferritin inclusion bodies found in transgenic mice and in individuals with HF. Expression of the transgene in mice leads to a significant decrease in motor performance and a shorter life span, formation of ferritin inclusion bodies, misregulation of iron metabolism, accumulation of ubiquitinated proteins, and incorporation of elements of the proteasome into inclusions. This new transgenic mouse represents a relevant model of HF in which to study the pathways that lead to neurodegeneration in HF, to evaluate the role of iron mismanagement in neurodegenerative disorders, and to evaluate potential therapies for HF and related neurodegenerative diseases.
Key words: neurodegeneration; hereditary ferritinopathy; nuclear inclusion; CNS; iron; ferritin
Received Aug. 29, 2007; revised Oct. 17, 2007; accepted Nov. 1, 2007.
Correspondence should be addressed to Dr. Ruben Vidal, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MSB A136, Indianapolis, IN 46202. Email: rvidal{at}iupui.edu
This article has been cited by other articles:
E. E. Benarroch
Brain iron homeostasis and neurodegenerative disease
Neurology, April 21, 2009; 72(16): 1436 - 1440.
[Full Text] [PDF]
M. A. Baraibar, A. G. Barbeito, B. B. Muhoberac, and R. Vidal
Iron-mediated Aggregation and a Localized Structural Change Characterize Ferritin from a Mutant Light Chain Polypeptide That Causes Neurodegeneration
J. Biol. Chem., November 14, 2008; 283(46): 31679 - 31689.
[Abstract] [Full Text] [PDF]
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