Struktur und Efferenzen der Substantia nigra pars compacta beim idiopathischen Parkinson-Syndrom

Falkenburger, Björn H.; Jost, Wolfgang H.; Ransmayr, Gerhard; Riederer, Peter; Winkler, Christian

doi:10.1055/a-1149-9280

Cited by 4 publications

(5 citation statements)

References 82 publications

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“…The reviews on these topics by Rietdijk et al ( 2017 ), Visanji et al ( 2013 ), Riederer et al ( 2019 , 2021 ), Jellinger ( 2019b ), and Urban et al ( 2020 ) point to the conclusion, that LBs pathology is an important factor but at least in sporadic PD is rather a disease progression as well as pathological multiplication factor. In addition, the “brain-first-hypotheses” are able to explain the laterality (Riederer et al 2018 ) of early PD pathology as the pathology may start predominantly in one hemisphere, while the bottom-up-hypothesis rather suggests a symmetrical brain pathology (Borghammer and Van Den Berge 2019 ).…”

Section: A Closer Look At ɑ-Synuclein and Lbsmentioning

confidence: 99%

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Riederer

Nagatsu

Youdim³

et al. 2023

J Neural Transm

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Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of “Parkinson’s disease (PD).” The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors—contributing with different ratios—appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in “brain-first” cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in “brain-first” cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the “bottom-up/dual-hit” and “brain-first” models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.

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Section: A Closer Look At ɑ-Synuclein and Lbsmentioning

confidence: 99%

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Riederer

Nagatsu

Youdim³

et al. 2023

J Neural Transm

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“…However, the Braak's "bottom-up hypothesis" has been challenged [106], since only in about 50% PD patients can it be attributed to gastro-intestinal triggering of the disease. Recently, the "top-down hypothesis" has been postulated, suggesting that the disease process starts due to cortical-striatal excitatory stress, leading to synaptic dysfunction and followed by a striatonigral retrograde process, including α-synuclein pathology [6,177]. Furthermore, the "threshold hypothesis" suggested by Engelender and Isacson [178] collectively considers various vulnerability sources including lysosomal clearing functions, different anatomical structures, cell types, and genetic factors [85,179].…”

Section: Neuroinflammationmentioning

confidence: 99%

“…Furthermore, the "threshold hypothesis" suggested by Engelender and Isacson [178] collectively considers various vulnerability sources including lysosomal clearing functions, different anatomical structures, cell types, and genetic factors [85,179]. The characteristic manifestation of asymmetric degeneration in PD [180] may be better explained by the "threshold hypothesis" in contrast to the "bottom-up hypothesis" [6]. The build-up of α-synuclein aggregates may prompt microgliosis and recruit CD4+ and CD8+ T cells.…”

Section: Neuroinflammationmentioning

confidence: 99%

“…The absence of motor symptoms may be due to the operation of some compensatory neuroplasticity mechanisms or the lack of some other factor(s), or a more significant nigral cell loss is required to progress to the symptomatic phase. Axon terminals may be the culprit of triggering the degenerative neuronal process in a retrograde manner, since α-synuclein is involved in the exocytosis of presynaptic vesicles [5,6]. Indeed, early symptoms are evident in around 50-60% of nigro-striatal axon terminal degeneration; in contrast, there is only about 30% loss of neuromelanin (NM) containing dopaminergic neurons in the SN [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Axon terminals may be the culprit of triggering the degenerative neuronal process in a retrograde manner, since α-synuclein is involved in the exocytosis of presynaptic vesicles [5,6]. Indeed, early symptoms are evident in around 50-60% of nigro-striatal axon terminal degeneration; in contrast, there is only about 30% loss of neuromelanin (NM) containing dopaminergic neurons in the SN [6,7]. The SN neuronal loss in the early asymptomatic stages of the illness can be attributed to the operation of degenerative processes such as oxidative stress (OS) triggered by misfolded α-synuclein.…”

Section: Introductionmentioning

confidence: 99%

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The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Sian-Hülsmann

Riederer

2021

Cells

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The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

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

et al. 2021

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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.

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Struktur und Efferenzen der Substantia nigra pars compacta beim idiopathischen Parkinson-Syndrom

Cited by 4 publications

References 82 publications

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

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

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