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.
Highlights
Parkinson’s disease (PD) is identified as the second most prevalent neurodegenerative disorder in the world, and it is an age-related progressive disease [1]
The main characteristic feature associated with PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and these neurons are the principal source of dopamine (DA), a neurotransmitter that regulates motor behavior [3]
PD etiology is linked to the presence of cellular inclusions, known as Lewy bodies (LBs), which have been identified as postmortem hallmarks of PD [4, 5]
Summary
Parkinson’s disease (PD) is identified as the second most prevalent neurodegenerative disorder in the world, and it is an age-related progressive disease [1]. It can be postulated that binding of iron at the C-terminus of αS (pI of 4.7) causes a neutralization of the negative charges [36] Such charge pairing can result in electrostatic shielding, which may impact protein folding dynamics by further altering the structure upon protein oxidation, crosslinking, aggregation, etc. We reported evidence to support the ferrireductase activity of αS upon binding to iron(III) under anaerobic conditions as well as an increase in the antiparallel β-sheet composition as is characteristic of αS aggregates formed under oxidizing conditions in the presence of FeII [18]. Detection of iron in these regions could be acknowledged as an indirect biomarker for PD
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