Misfolding of the
protein α-
synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to
Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-
synuclein has the potential to operate as the
enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of
alpha-synuclein/
ferrireductase invokes the dyshomeostasis of
iron (III)/(II) only, while in advanced stages, accumulation of
iron in particular areas of the brain follows. Furthermore, the loss of an important
iron chelator,
neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free
iron.
Iron could generate
reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of
enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the
ferrireductase alpha-synuclein may hold the key for major pathology of
Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-
synuclein/
ferrireductase causes
iron dyshomeostasis without increase of free
iron concentration in the early phases of PD, while increased
iron concentration accompanied by
iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of
iron chelators seems to be a reasonable approach.