Visualization of early oligomeric α‐synuclein pathology and its impact on the dopaminergic system in the (Thy‐1)‐h[A30P]α‐syn transgenic mouse model

Abstract

The histopathological hallmark of the Parkinson's disease (PD) brain is the presence of Lewy bodies (LBs) and Lewy neurites (LNs), intraneuronal lipid-and protein-rich complexes mainly consisting of fibrillar alpha-synuclein (α-syn) (Spillantini et al., 1997). Misfolding of native α-syn causes dynamic changes in its conformation, leading to formation of oligomers followed by protofibrillar species and finally

Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson’s disease

“…Another study successfully detected αSYN oligomers in transgenic mice (Thy1-h-αSYN*A30P) with αSYN-PLA similar to those employed in the present study. Of note, no signal was observed in the non-transgenic control mice [ 5 ].…”

Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils

“…Considering that dopamine is involved in novelty processing and can enhance hippocampal synaptic plasticity [47] , [48] , [49] , [50] , spreading of α-syn pathology throughout regions interconnected with dopaminergic areas most likely contributes to abnormalities in dopamine-dependent neuromodulation of cognitive processes. However, as we previously found that the levels of dopamine or its metabolites are unchanged in Thy-1-h[A30P] α-syn tg mice [51] , such an effect may possibly instead be the result of a harmful interaction between α-syn and either dopamine itself or its receptors.…”

Monitoring α-synuclein aggregation

“…It has particular relevance when it comes to exploring post-mortem tissue surfaces. In some cases, the liability and heterogenicity of early aggregates limit the use of traditional immunohistochemistry with conformational antibodies ( Behere et al, 2021 ). Others might claim that antigen preservation is not the issue but rather the limited knowledge of the conformers in the tissue.…”

“…Over the past few years, AS-PLA became a popular tool to study what authors usually termed early α-syn oligomers. It has been applied to study oligomer distribution in the midbrain of young mice ( Behere et al, 2021 ) or the brain samples of MSA and PD patients ( Sekiya et al, 2019 ). Bengoa-Vergniory and colleagues used AS-PLA in several models and situations to evaluate the presence of oligomers upon treatment with the molecular tweezer CLR01: PD patients' brain extracts, human dopaminergic cultures over-expressing α-syn, and human α-syn-overexpressing mouse model tissue ( Bengoa-Vergniory et al, 2020 ).…”