Publications by authors named "J Sian-Hülsmann"

8 Publications

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

J Neural Transm (Vienna) 2021 Oct 12;128(10):1577-1598. Epub 2021 Oct 12.

Department of Medical Physiology, University of Nairobi, P.O. Box 30197, Nairobi, 00100, Kenya.

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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http://dx.doi.org/10.1007/s00702-021-02414-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507512PMC
October 2021

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

Cells 2021 03 9;10(3). Epub 2021 Mar 9.

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy Margarete-Hoeppel-Platz 1, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.

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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http://dx.doi.org/10.3390/cells10030598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000327PMC
March 2021

The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson's disease.

J Neural Transm (Vienna) 2020 05 21;127(5):749-754. Epub 2020 Apr 21.

University Hospital Wuerzburg, Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany.

Misfolding of the protein α-synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-synuclein has the potential to operate as the enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of alpha-synuclein/ferrireductase invokes the dyshomeostasis of iron (III)/(II) only, while in advanced stages, accumulation of iron in particular areas of the brain follows. Furthermore, the loss of an important iron chelator, neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free iron. Iron could generate reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the ferrireductase alpha-synuclein may hold the key for major pathology of Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-synuclein/ferrireductase causes iron dyshomeostasis without increase of free iron concentration in the early phases of PD, while increased iron concentration accompanied by iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of iron chelators seems to be a reasonable approach.
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http://dx.doi.org/10.1007/s00702-020-02192-0DOI Listing
May 2020

Lateralisation in Parkinson disease.

Cell Tissue Res 2018 Jul 14;373(1):297-312. Epub 2018 Apr 14.

Parkinson Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.

Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson's disease compared to other forms of neurodegenerative or symptomatic parkinsonism. Even 200 years after the first description of the disease, the underlying causes for this striking clinicopathological feature are not yet fully understood. There is increasing evidence that lateralisation of disease is due to a complex interplay of hereditary and environmental factors that are reflected not only in the concept of dominant hemispheres and handedness but also in specific susceptibilities of neuronal subpopulations within the substantia nigra. As a consequence, not only the obvious lateralisation of motor symptoms occurs but also patterns of associated non-motor signs are defined, which include cognitive functions, sleep behaviour or olfaction. Better understanding of the mechanisms contributing to lateralisation of neurodegeneration and the resulting patterns of clinical phenotypes based on bilateral post-mortem brain analyses and clinical studies focusing on right/left hemispheric symptom origin will help to develop more targeted therapeutic approaches, taking into account subtypes of PD as a heterogeneous disorder.
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http://dx.doi.org/10.1007/s00441-018-2832-zDOI Listing
July 2018

Neurochemical markers as potential indicators of postmortem tissue quality.

Handb Clin Neurol 2018 ;150:119-127

Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Premortem, postmortem, and storage conditions are parameters that can influence the quality and interpretation of data from studies of postmortem tissue. While many neurochemicals in the brain are relatively stable for several hours after death if stored at 4°C, the postmortem delay nevertheless becomes an important variable when examining the disease state because neurochemical levels may change with extended postmortem delay. Moreover, in the postmortem brain, neurochemical levels may also play a key role in determining the diagnosis. This is particularly true for some neurodegenerative disorders where many of the clinical features of the disease are not exclusive to one illness. It is therefore imperative to employ brain tissue of the highest quality from both nondiseased (control) and diseased brain tissue to ascertain the specific molecular and genetic mechanisms particular to the disease pathogenesis. Consequently, it would be very useful if specific markers could be employed to demonstrate and determine the quality of postmortem brain tissue that is suitable for such studies. In this chapter, the following neurochemical markers are critically reviewed as potential candidates to assess the quality of postmortem brain tissue: tryptophan levels, glutathione levels (and glutathione metabolic enzymes), enzymatic activities (glutamate decarboxylase, phosphofructokinase-1), epigenetic enzymes (acetyltransferase, methyltransferase), and tissue pH. In conclusion, the neurochemical tryptophan appears to be the most suitable candidate for assessing the integrity and quality of postmortem brain tissue. However, to optimize the quality of the samples, neuropathologic diagnostic characterization must also be employed in the interpretation and understanding of the data generated. It would also be judicious to consider as many premortem and postmortem conditions as possible as they can also affect the genetic and molecular integrity of the brain tissue.
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http://dx.doi.org/10.1016/B978-0-444-63639-3.00009-8DOI Listing
August 2018
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