This post is about iron in the brain. Metals in the brain have been on the “who’s hot who’s not” list so many times — I threw out aluminum cookware at least once. Then it was non-stick.
Nevertheless, I check into brain-metal research every so often. One of my secret plans is to harness neuromelanin — the dark melanin pigment in your brain — that is a great electrical conductor. Something like putting a USB port into my substantia nigra and just forgetting the qwerty gig. On second thought, that would result in a totally random stream of consciousness that could probably be misinterpreted by homeland security or someone. Well, you get the drift: if we have this great conductive material in the brain, we should be able to plug something into it. Sort of Uncle Fester-style.
OK. Neuromelanin is found in the dark matter in the brain, the substantia nigra. If myelination is the insulation, I view substantia nigra as the conductive metal wiring. Parts are rich in iron, and the neuromelanin that binds iron. The substantia nigra (pars) is the wiring transferring electrical signal energy from deep within the brain to the outer branches where the synapses spark.
Neuromelanin is both a blessing and a curse. Iron-containing neuromelanin has something of a protective effect for neurons (here), presumably by preventing the oxidation of dopamine into toxic degradation products. Yet, neuromelanin can be toxic, like by inducing inflammation via immune response (in microglia).
Usually, with molecules that carry around a metal, the whole point is to transfer the metal elsewhere to release energy. There are these molecules that sit on the surface of a cell called transferrins, for example. Lactoferrin — one of the transferrins — is both an anti-microbial + anti-viral as well as an energy donor. This is why, for example, if you are doing your tomato gardening, you should dip your implements in diluted powdered milk — it contains lactoferrin that will kill off any viruses (like the tobacco mosaic virus, I think) that could infect your tomato plants. (Unhelpful advice at the end of summer. Sorry.)
In Parkinson’s disease, neuromelanin-containing dopaminergic neurons are wiped out. The whole thing seems to me to be related to iron in the brain. Brain iron homeostasis is a sticky wicket — there is a line of research into how iron is transported in the brain, and all the upstream players that carry the iron-ball around to get it where it needs to go. If one of these molecules is out of whack it could drop the ball, or hand it off to the wrong player, and poof- out goes the dopaminergic neurons in the substantia nigra. So you get Parkinson’s or something like it. See, Parkinson’s disease: Iron accumulation to the point of demise
The boringly named “divalent metal transporter -1″ (“DMT1″) and the Addams-familyish sounding Nedd4 family-interacting protein 1 (“Ndfip1″) are involved in brain iron transport, and there are a number of different forms of these genes (e.g., here). Plus, Nedd4 itself is involved in clean-up (ubiquinating), and it can be misfolded pretty easily — leading to lack of clean up, a bunch of gunk in the brain, and no iron transport. Where there is no Ndfip1 to bind to DMT1 and result in ubiquination (vacuuming out, from the Nedd4 ubiquitin ligase) of iron, there is iron toxicitity in the brain.
So it may be that in neurodegenerative diseases involving the substantia nigra, the iron transport team is the gang that can’t shoot straight. Iron delivery or removal in the neurons is messed up and the cells are either toxically overloaded, or anemically undernourished.
Here is “That Old Black Magic” sung by Ray Davies (via Yahoo music, supposed to be free, click through)
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