Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson's disease.
While ferritin elevation within dopaminergic (DA) neurons of the substantia nigra (SN) is protective against neurodegeneration elicited by two toxin models of Parkinson's disease (PD), MPTP and paraquat, in young animals, its prolonged elevation results in a selective age-related neurodegeneration. A similar age-related neurodegeneration has been reported in iron regulatory protein 2-deficient (IRP2 -/-) mice coinciding with increased ferritin levels within degenerating neurons. This has been speculated to be due to subsequent reductions in the labile iron pool (LIP) needed for the synthesis of iron-sulfur-containing enzymes. In order to assess whether LIP reduction is responsible for age-related neurodegeneration in our ferritin transgenics, we examined LIP levels in ferritin-expressing transgenics with increasing age. While LIP levels were reduced within DA SN nerve terminals isolated from young ferritin transgenics compared to wildtype littermate controls, they were found to be increased in older transgenic animals at the age at which selective neurodegeneration is first noted. Furthermore, administration of the bioavailable iron chelator, clioquinol (CQ), to older mice was found to protect against both increased LIP and subsequent dopaminergic neurodegeneration. This suggests that age-related neurodegeneration in these mice is likely due to increased iron availability rather than its reduction. This may have important implications for PD and other related neurodegenerative conditions in which iron and ferritin have been implicated.
Kaur
Deepinder
D
Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945, USA.
Rajagopalan
Subramanian
S
Andersen
Julie K
JK
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D002614:Chelating Agents; D007464:Clioquinol; D001052:Apoferritins; D007501:Iron; D004298:Dopamine
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