McLean, P. J. | Search bioRxiv

bioRxiv2024

Widespread Distribution of α-Synuclein Oligomers in LRRK2-related Parkinson's Disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinsons disease (PD). While the clinical features of LRRK2-PD patients resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of -synuclein (SYN)-positive Lewy-related pathology; however, approximately half of LRRK2-PD cases do not have Lewy-related pathology. Lewy-related pathology is a late-stage SYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that SYN oligomers, which represent the early-stage of SYN aggregation, may have neurotoxicity. Visualization of SYN oligomers requires specialized staining techniques, such as SYN-proximity ligation assay (PLA). The distribution and severity of SYN oligomers in the human brain of LRRK2-PD patients remain unknown. In this study, we performed phosphorylated SYN-IHC and SYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (n=5), p.I2020T (n=5), and p.R1441C (n=4). The severity of Lewy-related pathology and SYN oligomers were assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. SYN oligomers were detected in LRRK2-PD cases even in cases without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and SYN oligomers (r=-0.26 [-0.39, -0.12]; P<0.0001). Our findings suggest that SYN oligomers may represent a common pathological feature of LRRK2-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of SYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These cases also had a trend toward shorter disease duration. These results imply that in LRRK2-PD, SYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting SYN oligomers may be a therapeutic strategy for LRRK2-PD even if there is no Lewy-related pathology.

neuroscience↗

bioRxiv2023

Honokiol decreases alpha-synuclein mRNA levels and reveals novel targets for modulating alpha-synuclein expression.

Neuronal inclusions comprised of aggregated alpha-synuclein (syn) represent a key histopathological feature of neurological disorders collectively termed "synucleinopathies", which includes Parkinsons disease (PD). Mutations and amplifications in the SNCA gene encoding syn cause familial forms of PD and a large body of evidence indicate a correlation between syn accumulation and disease. Decreasing syn expression is recognized as a valid target for PD therapeutics, with down-regulation of SNCA expression potentially attenuating downstream cascades of pathologic events. Honokiol (HKL) is a polyphenolic compound derived from magnolia tree bark that has demonstrated neuroprotective properties. Here, we describe potential beneficial effects of HKL on syn levels in multiple experimental models. Using human neuroglioma cells stably overexpressing syn and mouse primary neurons, we demonstrate that HKL treatment results in a significant decrease in syn expression at both the protein and mRNA levels. Our data support a mechanism whereby HKL acts by post-transcriptional modulation of SNCA rather than modulating syn protein degradation. Additionally, transcriptional profiling of mouse cortical neurons treated with HKL identified several differentially expressed genes (DEG) as potential targets to modulate SNCA expression. Overall, these data highlight a viable strategy to reduce syn levels, which represents a promising target to modify disease progression in PD and other synucleinopathies. In addition, HKL acts as a powerful tool for investigating SNCA gene modulation and its downstream effects.

neuroscience↗