Paper
- Alzforum Recommends
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Feb;18(2):291-5. PubMed.
Recommends
Please login to recommend the paper.
Comments
Pennsylvania State University College of Medicine
This paper by Lei et al. provides two important novel observations. Firstly, as a parkinsonian model, the tau knockout mice are exciting because they do not show symptoms of disease until 12 months of age; thus, similar to Parkinson’s patients, there is an age dependency for symptom onset and presumably host vulnerability. Secondly, the data demonstrate that tau itself is not the culprit but an age-dependent accumulation of iron because tau has been absent from birth in the mice but symptom onset is not until iron levels reach a threshold level. Therefore, the role of iron in the pathogenesis of Parkinson's becomes even stronger. Moreover, the data continue to implicate amyloid-β precursor protein (APP) in the neuronal regulation of iron; although one can wonder why, given the reported importance of APP as a neuronal exporter of iron, it would take 12 months for enough iron to accumulate to see an effect. It would be informative to know the expression of ferritin in the neurons. Ferritin could offer protection from the iron by sequestering it. A number of years ago we had argued that it is not iron that is problematic for cells, but the mismanagement of iron, including in Parkinson’s brains (Connor et al., 1995). The accumulation of ferritin could be expected to have limited impact in acute models of tyrosine hydroxylase neuronal degeneration in response to toxin injections, but in a chronic model, as in the tau knockout mice of Lei et al., a failure of ferritin expression and protection could provide insights into how iron accumulation is problematic. Loss of ferritin may also explain why the cells do not respond better to the iron accumulation by protecting themselves and provide potential targets for therapy. If ferritin could be induced, would it be protective in this model? It was shown that expression of ferritin in tyrosine hydroxylase neurons protects them from MPTP (Kaur et al., 2003). Maybe the cells do express ferritin, but over time the amounts of ferritin become insufficient to offer protection.
The tau knockout animal model could also be valuable in providing MRI data that could help answer when, in the time frame of symptom onset, iron accumulation in the SN begins. This is important, since the clioquinol was given beginning at 6.5 months for five months. It is remarkable that over the length of time this drug was present, there was no loss of liver iron, or that neither copper nor zinc levels were affected by this drug.
This study joins a number of others on various degenerative diseases or models such as stroke, ALS, and multiple sclerosis in demonstrating that providing an iron chelator prior to the onset of damage or disease was protective. Thus, there is a long line of evidence that limiting iron is beneficial. The challenge ahead is to determine if the iron reverses or rescues symptoms similar to the single dose of L-DOPA. For now, we have a new, exciting animal model that continues to support the findings that APP has important ferroxidase activity in the brain, and that mutations in proteins as important as tau require additional factors, such as iron accumulation, to induce neurodegeneration. The data also strongly argue that iron is pathogenic in PD and not a bystander effect secondary to neurodegeneration.
References:
Connor JR, Snyder BS, Arosio P, Loeffler DA, Lewitt P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J Neurochem. 1995 Aug;65(2):717-24. PubMed.
Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, Dimonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron. 2003 Mar 27;37(6):899-909. PubMed.
Make a Comment
To make a comment you must login or register.