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


Journal

Journal of neural transmission (Vienna, Austria : 1996)
ISSN: 1435-1463
Titre abrégé: J Neural Transm (Vienna)
Pays: Austria
ID NLM: 9702341

Informations de publication

Date de publication:
05 2023
Historique:
received: 13 03 2023
accepted: 29 03 2023
medline: 25 4 2023
pubmed: 17 4 2023
entrez: 16 4 2023
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 37062012
doi: 10.1007/s00702-023-02630-9
pii: 10.1007/s00702-023-02630-9
pmc: PMC10121516
doi:

Substances chimiques

neuromelanin 0
Iron E1UOL152H7
alpha-Synuclein 0

Types de publication

Journal Article Review Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

627-646

Informations de copyright

© 2023. The Author(s).

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Auteurs

Peter Riederer (P)

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany. jntspringer@web.de.
Department of Psychiatry, University of Southern Denmark Odense, J.B. Winslows Vey 18, 5000, Odense, Denmark. jntspringer@web.de.

Toshiharu Nagatsu (T)

Center for Research Promotion and Support, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.

Moussa B H Youdim (MBH)

BioShai Ltd., 1 Ha‑Tsmikha St., Yokneam, Israel.

Max Wulf (M)

Medizinisches Proteom-Center, Medical Faculty, Ruhr-University Bochum, 44801, Bochum, Germany.
Medical Proteome Analysis, Center for Protein Diagnostics (PRODI), Ruhr-University Bochum, 44801, Bochum, Germany.

Johannes M Dijkstra (JM)

Center for Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

Jeswinder Sian-Huelsmann (J)

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

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