Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson’s disease

Abstract

About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson’s disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood–brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, “iron” is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.

Iron Metabolism in Aging and Age-Related Diseases

“…Lewy bodies are often found in the substantia nigra and are also present in neurodegenerative diseases, such as dementia with Lewy bodies [ 124 ]. Previous studies have shown that iron can stimulate intracellular α -synuclein and ubiquitin aggregation in PD patients [ 125 ]. There are toxic feedback loops of iron, reactive oxygen species, and α -synuclein in PD patients.…”

Interaction between macrophages and ferroptosis

“…Abundant evidence has proved the link between ferroptosis and neurological diseases, like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other brain injury [ 111 – 115 ], accompanied by the occurrence of neuroinflammation. A number of macrophages in nerve tissue, which are called Hortega cells or microglia cells, are involved in the regulation of neuroinflammation.…”

The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction

“…Evidence indicates that an altered BBB contributes to iron accumulation, particularly in substantia nigra and striatum, and neuroinflammation in PD models. Iron chelator treatment attenuated iron accumulation and suppressed neuroinflammation, which further decreased the BBB impairment and the damage of dopaminergic neurons ( Olmedo-Diaz et al, 2017 ; Tai et al, 2020 ; Han et al, 2021 ; Riederer et al, 2021 ; Zhao et al, 2021 ). And in disease animal models of AD, accumulation of iron can not only prompt the accumulation and aggregation of the Aβ and tau protein, but also induces ROS production in the brain of AD.…”