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

Abstract

The pathological hallmarks of Parkinson’s disease (PD) are α-synuclein (αSYN)-positive inclusions referred to as Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology (LRP). LRP is thought to propagate in an ascending manner throughout the brain as the disease progresses. LRP is visible with histologic methods and is thought to represent a later stage of the disease process, while αSYN oligomers, which are not visible with routine histologic methods, are considered earlier. There is increasing evidence to suggest that αSYN oligomers may be more toxic than visible LRP. Detecting αSYN oligomers requires special techniques, and their distribution and association with clinical features are important research objectives. In this report, we describe the distribution of αSYN oligomers in multiple cortical and subcortical regions of PD using a proximity ligation assay (PLA). We observe widespread distribution of αSYN oligomers with PLA and more restricted distribution of LRP with αSYN immunohistochemistry. The distribution of αSYN oligomers differed from LRP in that αSYN oligomer burden was significantly greater in the neocortex, while LRP was greater in vulnerable subcortical regions, including the brainstem. We also found that cognitive impairment was associated with αSYN oligomers in the hippocampus. These results suggest that αSYN oligomers may be widely distributed in PD early in the disease process and that they may contribute to cognitive impairment in PD.

The large neuron involvement in the neostriatum in Lewy body diseases

“…24 In addition, a possibility of toxicity of αsyn oligomers and some other pathomechanism affects the large neurons in the neostriatum in the PD and DLB would be considerable. [25][26][27] In conclusion, although the number of examined patients was small, the present study highlighted the reduction/shrinkage of the large cholinergic interneurons in the caudate nucleus and putamen in the patients with PD and DLB. The reduction of the number of the large neurons in PD or DLB might be caused by the accumulation of p-tau or p-αsyn within the soma of the cells and a certain other mechanism, such as accumulation of αsyn oligomer or transsynaptic degeneration due to loss of dopaminergic fibers from the substantia nigra.…”

Protein kinase R dependent phosphorylation of α-synuclein regulates its membrane binding and aggregation

“…Yet, the exact relationship between PKR activity and neuropathology will have to be addressed in a completely different set of experiments. In relation to α-syn aggregate pathology, it is worth noting recent data from PD patients, which demonstrate widespread distribution of α-syn oligomers in brain areas unaffected by LB pathology, and that cognitive impairment can be associated with the load of these α-syn oligomers in the hippocampus ( 73 ).…”

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…Sekiya et al [ 51 ] used proximity ligation assay—a new technique to detect the distribution of α-synuclein oligomers, compare the results with immunohistochemical data and analyze the correlation between the presence of oligomers with clinical features. The results show that α-synuclein oligomers are more widespread than Lewy-related pathology (LRP, Lewy bodies, and Lewy neurites) and that α-synuclein oligomers in the hippocampus correlate with cognitive impairment.…”