Iron Redox Chemistry and Implications in the Parkinson’s Disease Brain

Abstract

The etiology of Parkinson's disease (PD) is linked with cellular inclusions in the substantia nigra pars compacta region of the brain that are enriched in the misfolded presynaptic protein α-synuclein (αS) and death of the dopaminergic neurons. Brain iron homeostasis governs both neurotransmission and neurodegeneration; hence, the role of iron in PD progression and neuronal health is apparent. Elevated iron deposits become prevalent in the cerebral region upon aging and even more so in the PD brain. Structural as well as oxidative modifications can result from coordination of αS with redox active iron, which could have functional and/or pathological implications. In this review, we will discuss iron-mediated αS aggregation, alterations in iron metabolism, and the role of the iron-dopamine couple. Moreover, iron interactions with N-terminally acetylated αS, the physiologically relevant form of the human protein, will be addressed to shed light on the current understanding of protein dynamics and the physiological environment in the disease state. Oxidative pathways and biochemical alterations resulting from aberrant iron-induced chemistry are the principal focus of this review in order to highlight the plethora of research that has uncovered this emerging dichotomy of iron playing both functional and disruptive roles in PD pathology.

Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence

“…Conversely, there are many indications that iron overload and presence of unbound iron in cellular structure have deleterious consequences on mental health. Indeed, excessive iron deposits become prevalent in the cerebral region upon ageing and even more so in the brains of subjects suffering from Parkinson disease [179] or Alzheimer disease [180] diseases, where they are associated with the neurodegeneration observed in these pathologies.…”

The Potential for Natural Antioxidant Supplementation in the Early Stages of Neurodegenerative Disorders

“…Moreover, the reduction of the GSH levels and higher oxidative stress promote the aggregation of the α-synuclein protein [47]. According to some studies, that GSH supplementation led to the dissolution of the α-synuclein aggregates as well as to an increase in the GSH levels in the brains of rats with induced PD [48]. Clinical studies based on NMR proved the involvement of GSH in multiple sclerosis.…”

Mapping of Photochemically-Derived Dityrosine across Fe-Bound N-Acetylated α-Synuclein

“…Fe II supplementation resulted in a moderate decrease in the overall fluorescence emission of dityrosine crosslinks within NAc WT, while Fe III supplementation enhanced overall dityrosine crosslinking in NAc WT. Iron is thought to bind within the C-terminal region of NAc αSyn [9,18,24], within close proximity to the three C-terminal tyrosine residues. Previously, we reported that Fe blocks Cu-induced photoinitiated dityrosine crosslinking in NAc αSyn [23], and our current results further suggest that Fe II also results in a relative decrease in dityrosine crosslinking compared to the unmetalated native protein.…”

“…In contrast, Fe III coordination to NAc WT promotes a conformation of NAc αSyn that facilitates photoinitiated dityrosine crosslinking. Pathological concentrations of iron accumulate within the substantia nigra of PD afflicted patients [18]. To map the structural impact of iron coordination to NAc αSyn, NAc WT and each of the NAc αSyn tyrosine mutants were subjected to stoichiometric ratios of iron in both the Fe II and Fe III redox states (Figure 3).…”

“…External stimuli-metal binding, for example-can stabilize a particular structure that could have a downstream influence on a specific biological pathway. Metal dyshomeostasis has long been linked to PD [18][19][20], and victims of PD present with increased cerebral iron levels and diminished levels of copper in affected regions of the brain. Although the precise roles of brain metals on the function of NAc αSyn have yet to be elucidated, we [10,[21][22][23] and others [9,24,25] have demonstrated how prevalent brain biometals modulate the structural outcome of NAc αSyn self-assembly pathways and influence both the potential and the extent of its aggregation.…”