The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease

Abstract

In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal inter-group difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson’s disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Ferroptosis in Parkinson’s disease: glia–neuron crosstalk

“…Several mutations in ferroptosis genes have been linked to PD (Table 1), including DJ-1, autosomal recessive PD gene, that encodes a negative modulator of ferroptosis [16]. Moreover, the characteristics of ferroptosis induction are highly consistent with the pathological changes observed in PD patients, including increased iron content [4,5], lipid peroxidation [17][18][19], and defects in the antioxidant system such as decreased levels of cystine/ glutamate antiporter (xCT) [20], glutathione (GSH) [21], DJ-1 (that maintains cysteine and GSH biosynthesis) [16], and CoQ10 [22]. Furthermore, ferroptosis was observed in different PD cellular and animal models such as SH-SY5Y cells treated with MPP + and 6-OHDA, and MPTP-lesioned mice [8][9][10].…”

“…Activated glia may act as 'double-edged swords' because they can exert neuroprotective effects by releasing neurotrophic factors and phagocytosis, while mediating neuronal damage by releasing proinflammatory cytokines [3]. Brain imaging and pathological studies have shown correlations between iron deposition in the SNpc of PD patient brains and DA neuronal loss [4,5], indicating that imbalance of iron homeostasis may be a factor closely associated with neuronal death in PD. This type of iron-dependent cell death is termed ferroptosis [6].…”

Cerebral Iron Deposition in Neurodegeneration

“…Parkinson Disease ↓ Fe in serum/plasma [107] ↑ Fe in substantia nigra [108,109] ↑ Fe in neurons and adjacent neuropil, microglia, perivascularly in extracellular deposits [110][111][112] Fe bound to neuromelanin in dopaminergic neurons [112,113] Alzheimer Disease ↓ Fe in serum/plasma [114][115][116] ↑ Fe in (mostly temporal) cortex, globus pallidus, caudate, putamen [117][118][119][120][121][122] ↑ Fe in amyloid plaques, microglia, along myelinated fibers [117,[123][124][125] Fe bound to amyloid partially composed of magnetite nanoparticles [126,127] Amyotrophic Lateral Sclerosis ↑ ferritin, ↓ transferrin in serum [128] ↑ Fe in liver, kidneys [129] ↑ Fe in spinal cord [130,131] ↑ Fe in motor cortex, caudate, subthalamic nucleus, globus pallidus, substantia nigra, red nucleus [132][133][134] ↑ Fe in spinal cord neuron nuclei [135] ↑ Fe in microglia in motor cortex [136] n.a.…”

The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective

“…Apart from pathological protein inclusions, the brain is affected by a progressive alteration of its neurochemistry as well as an imbalance of numerous neurotransmitters that disturb the activity of neurons and glial cells. The progressive depletion of NA and dopamine (DA) is associated with ageing ( Manaye et al, 1995 ; Volkow et al, 1998 ; Beardmore et al, 2021 ) and the onset of NDDs such as AD and PD ( Weinshenker, 2018 ; Biondetti et al, 2021 ). A local change of availability of NA or DA could strongly alter the responses of astrocytes in NDDs and favor their neurotoxicity.…”