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Neuronal iron accumulation associated with tau deficiency in parkinsonism

Hyperphosphorylated forms of the microtubule-associated protein, tau, contribute to the pathogenesis of neurodegenerative diseases termed tauopathies. Because tau also has risk alleles for Parkinson’s disease (PD), the role of tau in the pathogenesis of PD and related disorders (so-called synucleinopathies) has recently attracted considerable attention. Neuronal iron accumulation has been observed pathologically in both tauopathies and synucleinopathies and its role in neurodegeneration has been debated. In an article recently published in Nature Medicine, Lei et al. reported that aged tau-deficient mice developed motor and cognitive dysfunction that was linked to the impairment of amyloid precursor protein (APP)-mediated iron export. First, they evaluated the soluble tau and iron levels in PD models and found a reciprocal association between changes in SN tau and iron over 45 days in MPTP-treated mice. They hypothesized that the gradual loss of iron homeostasis in the SN after MPTP treatment might be caused by upstream tau loss and that this could lead to SN degeneration. To test this hypothesis, they examined the motor functions, brain iron levels, and histopathological changes in the brains of tau knock-out (KO) mice. In 12-month-old tau KO mice, there were 40% fewer dopaminergic neurons in the SN pars compacta, which was consistent with the onset of a parkinsonian phenotype. Furthermore, iron levels were 22% higher in the SN of 12-month-old tau KO mice, compared to agematched wild-type (WT) mice. They confirmed that the ironefflux rate was significantly lower in primary neurons from tau KO mice than in neurons from WT mice. Based on a previous finding, that the function of neuronal iron export depends on the interaction of ferroportin with APP at the neuronal surface, they examined the subcellular localization of APP in primary neurons. Indeed, the amount of APP at the neuronal surface was markedly reduced in tau KO mice. Interestingly, adding soluble APP (695 alpha) to the culture suppressed iron accumulation in tau KO neurons. Finally, an evaluation of cell viability revealed that the half-maximal lethal dose for Fe (II) toxicity was 57% lower for tau KO neurons than for WT neurons. Because iron accumulation can increase oxidative-stress– induced neuronal vulnerability, the discovery of dysfunctional APP-mediated iron export in aged tau-deficient mice may have a big effect on the development of disease-modifying therapies for neurodegenerative diseases. Synergistic interactions between the tau deficiency, iron accumulation, and alpha-synuclein pathology would be worth investigating in the future.