Iron and cell death in Parkinson's disease: a nuclear microscopic study into iron-rich granules in the parkinsonian substantia nigra of primate models

Parkinson's disease is a degenerative brain disease characterised by a loss of cells in the substantia nigra (SN) region of the brain and accompanying biochemical changes such as inhibition of mitochondrial function, increase d iron concentrations and decreased glutathione levels in the parkinsonian SN. Though the aetiology of the disease is still unknown, the observed bioc hemical changes point to the involvement of oxidative stress. Tn particular , iron is suspected to play a role by promoting free radical production, le ading to oxidative stress and cell death. The increase in iron in the parki nsonian SN has been confirmed by several research groups, both in human pos t-mortem brains and in brain tissue from parkinsonian animal models. Howeve r, the question remains as to whether the observed increase in iron is a ca use or a consequence of the SN cell death process. Our previous study using unilaterally l-methyl-l-phenyl-l,2,3,6-tetrahydro-pyridine (MPTP)-lesioned monkeys in a time sequence experiment has shown that the increase in bulk iron concentrations follow rather than precede dopaminergic cell death. However, changes in the localised iron concentrations, which may play a mor e direct role in SN cell death, may not be reflected at the bulk level. Ind eed, we have observed iron-rich granules in parkinsonian SNs. From this tim e sequence study into the iron content of iron-rich granules in the SNs of an untreated control and unilaterally MPTP-lesioned parkinsonian models, we present the following observations: (1) Iron-rich granules are found in bo th control and parkinsonian SNs and are variable in size and iron content i n any one model. (2) These iron-rich granules may be associated with neurom elanin granules found in the SN and are known to accumulate transition meta l ions such as iron. (3) The early onset of bulk SN cell loss (35%) was acc ompanied by a. significant elevation of iron in granules found in the MPTP- injected SN compared to the contra-lateral SN. This shows that localised ir on increase may be an early event contributing to cell death. (4) The iron content in granules found in both the MPTP-injected and contra-lateral SNs is correlated with the degree of bulk SN cell loss (assessed by TH-immunohi stochemistry) in individual models. This indicates a correlation between lo calised iron increase and cell loss, at least at the whole SN level.