Research ReportChronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration
Introduction
Increased ferritin levels have been reported by some laboratories to occur in the substantia nigra (SN) of Parkinsonian patients, the midbrain region preferentially impacted by the disorder (Bartzokis et al., 2004, Griffiths et al., 1999). Targeted disruption of the gene encoding iron regulatory protein 2 (IRP2) in mice is also associated with, among several other changes, an increase in ferritin levels along with a substantial accumulation of iron in the central nervous system proceeding onset of a progressive age-related ataxic movement disorder (LaVaute et al., 2001). Neuroferritinopathy, a recently recognized human genetic disease resulting in an age-dependent progressive movement disorder, also appears to involve abnormal ferritin accumulation in the brain (Crompton et al., 2002, Curtis et al., 2001). While ferritin increase is correlated with neurodegeneration in both human disease and the IRP2 knockout mouse model, many other alterations also occur which could conceivably be responsible for ensuing age-related neurodegeneration. Previously, we created transgenic mouse lines in which ferritin levels were selectively elevated within dopaminergic SN neurons resulting in an increase in ferritin-bound iron within these cells (Kaur et al., 2003). In young animals, this was found to afford protection against neurodegeneration associated with two widely used animal models of the disease, systemic 1-methyl-4-phenyl 2,3,6-tetrahydropyridine (MPTP) (Kaur et al., 2003) and paraquat administration (McCormack et al., 2005). Here, we examined the effects of chronic ferritin elevation in these neurons to explore whether its persistent elevation could be a direct cause of age-related neurodegeneration.
Section snippets
Results
As previously reported by our laboratory, ferritin transgenics display an elevation in dopaminergic SN iron levels by an early age (Kaur et al., 2003) which is found to be maintained into late adulthood. This represents an increase in both total iron levels as assessed by inductively coupled plasma mass spectroscopy (ICP-MS, Fig. 1A) and ferritin-bound iron as measured by magnetic resonance imaging (MRI, Fig. 1B). Although no neuropathology was previously observed in the younger (2–4 months)
Discussion
We report here that prolonged elevation of ferritin levels within dopaminergic midbrain neurons results in their progressive age-related neurodegeneration. This is initially manifested as a striatal axonopathy accompanied by loss in locomotor function and is followed by a significant loss in striatal dopamine content and subsequent SN dopaminergic cell loss. This transgenic line was originally created in our laboratory in order to assess the impact of alterations in intradopaminergic nigral
Animals
Construction and characterization of the ferritin transgenics and wildtype littermate controls used in this study were previously described (Kaur et al., 2003). Transgenics were constructed in the hybrid B6D2 background strain. The tyrosine hydroxylase (TH) promoter was used to drive human H ferritin expression in these mice. Both male and female mice were used in this study as no sex-dependent phenotypic differences were noted. Animals were bred in-house and housed according to standard animal
Acknowledgments
This work was funded by the National Institutes of Health grant NS41264 (JKA), NHMRC (Australia) and the Percy Baxter Trust (RAC) (RC).
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