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

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.

Investigating the neuroprotective potential of rAAV2‐PCBP1‐EGFP gene therapy against a 6‐OHDA‐induced model of Parkinson's disease

“…As PCBP1 is an iron chaperone, relevant study proposed that the lack of PCBP1 gave rise to higher levels of chemically reactive iron, which triggered an increase of reactive oxygen species that caused the mitochondrial damage. This study relevant with our study because iron accumulation in the substantia nigra has been implied in the pathophysiology of PD (Riederer et al, 2023;Youdim et al, 1993). Another study showing the role of PCBP1 in the regulation of genes associated with inflammation and ubiquitination (Yusufujiang et al, 2022), which have been implied in the pathogenesis of neurodegenerative disorders.…”

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

“…In addition, the presence of LBs may inherently confer toxicity to the cell either as mechanic disruptors of cell metabolism or even indirectly by triggering neuroinflammation. This phenomenon appears to play a significant role in PD [112]. In fact, LBs, as shown recently [113,114], foster the occurrence of neuroinflammation in PD and high IgG levels correlate with the amounts of LBs in PD patients.…”

Reanalysis of Orbitrap Astral DIA data demonstrates the capabilities of MS/MS-free proteomics to reveal new biological insights in disease-related samples

“…Anomalous metal distribution is characteristic of both neurodegenerative diseases in general and alpha-synucleinopathies, such as multiple system atrophy in particular. [17][18][19] Hence, examining the pathogenesis of this disease specifically focuses on the increase in iron concentration in subcortical brain structures in combination with the imbalance of iron metabolism regulator proteins. 20 Our analysis of samples from the prefrontal cortex revealed a decrease in the level of the protein P02792 (light chain of ferritin) relative to controls, as was previously demonstrated immunohistochemically in human brain samples.…”