Iron and neuromelanin in the nigra

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

E. Sofic, Peter Riederer and colleagues, University of Würzburg (1988); David Dexter, Peter Jenner, C. David Marsden and colleagues, Institute of Psychiatry, London (1989); Iria Carballo-Carbajal and colleagues, Vall d'Hebron Research Institute, Barcelona (Nat Commun 2019; Miquel Vila's group, not confirmed from the byline read).

What happened

• 1988. In a small post-mortem study (8 cases, 8 controls), Sofic et al. found nigral total iron up 176% and iron(III) up 225% in Parkinson's. A later review notes their method may have released iron from ferritin during preparation. No difference appeared in cortex, hippocampus, putamen or globus pallidus.
• 1989. Dexter et al. measured metals in post-mortem brain (7 Parkinson's, 9 controls, per the review) and found total nigral iron up 31–35%, with copper down and zinc up. A second Dexter paper found raised lipid peroxidation (damage to cell fats by free radicals) in the Parkinson's nigra. Not all studies agreed: Uitti (1989) and Loeffler (1995) saw no iron rise.
• 2019. Neuromelanin is the dark pigment made when dopamine is oxidised, and it binds iron. Lab rodents lack it. Carballo-Carbajal et al. made rats express human tyrosinase, which produced human-like neuromelanin that built up with age. Past a threshold, the rats showed slow movement, Lewy body-like inclusions and loss of nigral dopamine neurons. Boosting lysosomal clearance (enhancing the cell's recycling system) lowered neuromelanin and protected the cells.

Why it moved us toward a cure

This is the case for iron as a harm that could be removed, and is the parent of the deferiprone trial (landmark 67). It also builds on the finding that dopamine oxidises into toxic products (landmark 58) in the neurons that die first (landmark 1). The neuromelanin model explains why those cells are vulnerable and suggests clearing the pigment as a different approach.

Outcome

Open. The iron-removal approach failed in humans (deferiprone worsened symptoms), but the neuromelanin idea is untested in people.

Sources

• Sofic E et al., "Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain", J Neural Transm 1988;74:199-205, DOI 10.1007/BF01244786, PMID 3210014 (abstract)
• Dexter DT et al., "Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease", J Neurochem 1989;52:1830-1836, DOI 10.1111/j.1471-4159.1989.tb07264.x, PMID 2723638 (abstract)
• Dexter DT et al., "Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease", J Neurochem 1989;52:381-389, DOI 10.1111/j.1471-4159.1989.tb09133.x, PMID 2911023 (abstract)
• Friedman & Galazka-Friedman, "The history of the research of iron in parkinsonian substantia nigra", J Neural Transm 2012;119:1507-1510 (PMC3505548) (sample sizes and the Uitti and Loeffler results)
• Carballo-Carbajal I et al., "Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis", Nat Commun 2019;10:973, DOI 10.1038/s41467-019-08858-y, PMID 30846695 (abstract; open copy)
• Not yet verified: the full texts of all three papers (abstracts only); Uitti and Loeffler originals (read via the 2012 review); that deferiprone worsened symptoms (taken from landmark 67); the claim that iron is raised in life on MRI.