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Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson's disease.
| Content Provider | Europe PMC |
|---|---|
| Author | Riederer, Peter Nagatsu, Toshiharu Youdim, Moussa B. H. Wulf, Max Dijkstra, Johannes M. Sian-Huelsmann, Jeswinder |
| Abstract | 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. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10121516&blobtype=pdf |
| ISSN | 03009564 |
| Journal | Journal of Neural Transmission [J Neural Transm (Vienna)] |
| Volume Number | 130 |
| DOI | 10.1007/s00702-023-02630-9 |
| PubMed Central reference number | PMC10121516 |
| Issue Number | 5 |
| PubMed reference number | 37062012 |
| e-ISSN | 14351463 |
| Language | English |
| Publisher | Springer Vienna |
| Publisher Date | 2023-04-16 |
| Publisher Place | Vienna |
| Access Restriction | Open |
| Rights License | Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2023 |
| Subject Keyword | Parkinson’s disease Iron Lewy bodies Inflammation Neuromelanin Pathology α-synuclein |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neurology Biological Psychiatry Neurology (clinical) Psychiatry and Mental Health |
