Martin Ingelsson, Sweden
Uppsala University Department of Public Health and Caring Sciences/GeriatricsAuthor Of 2 Presentations
ACCUMULATION OF ALPHA-SYNUCLEIN WITHIN THE LIVER: A POTENTIAL FEATURE IN THE PATHOGENESIS OF PARKINSON’S DISEASE AND RELATED SYNUCLEINOPATHIES
Abstract
Aims
The aim of this study is to investigate whether the liver is susceptible to α-syn accumulation in Parkinson’s disease (PD).
Methods
We assessed whether α-syn assemblies could be internalized by cultured primary human and HuH-7 hepatocytes. We then characterized human α-syn in liver tissue samples from transgenic models modeling PD, multiple system atrophy and Alzheimer’s disease (AD). Finally, we corroborated our results in human PD using imaging techniques.
Results
We demonstrate that human hepatocytes internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin 32 (Cx32). Moreover, we identified a time dependent accumulation of α-syn pathology within the liver of three different transgenic mouse models overexpressing human α-syn under CNS-specific promoters. Such a brain to liver transmission route could be corroborated by detection of α-syn pathology within the liver of wild type mice one-month after a striatal α-syn injection. Notably, accumulation of Aß pathology in mice modeling AD was relatively absent. Consistent with our models, we identified the presence of α-syn pathology in a subset of human liver tissues from cases neuropathologically diagnosed with α-syn in the brain.
Conclusions
Our preliminary observations reveal α-syn pathology accumulation within the liver in a subset of human PD cases and mice modeling PD, a pathological process unique tothe synucleinopathies as pathology associated with AD is relatively absent. These results suggest that α-syn liver accumulation is likely a consequence of brain to liver or peripheral-liver transmission. Thus, the liver may be involved in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.
TOPMED-IMPUTED GENOME-WIDE ASSOCIATION STUDY OF ALZHEIMER’S DISEASE IN THE EADB PROJECT
Abstract
Aims
Strong efforts are still needed to characterize the genetic architecture of Alzheimer’s disease (AD). We thus conducted a complementary genome-wide association study (GWAS) with increased sample size and improved imputation quality of low frequency variants by applying the new TOPMed imputation panel.
Methods
The GWAS was performed in the European Alzheimer Disease Biobank (EADB) dataset. It groups together the main European AD GWAS consortia and a new dataset of 20,464 AD cases and 22,244 controls of European ancestry. Imputation was performed with the TOPMed reference panel or with the Haplotype Reference Consortium panel. The EADB results were meta-analysed with a proxy-AD GWAS performed in the UK Biobank, leading to a total Stage 1 sample size of 39,106 clinically diagnosed AD cases, 46,828 proxy-AD cases and 401,577 controls. The best hits from Stage 1 were finally tested in a large set of independent samples from ADGC and CHARGE.
Results
We identified 65 loci with a genome-wide significant signal of association (P<5x10-8), including 31 new AD loci. The most significant gene sets identified by a pathway analysis relate to amyloid-beta and tau, while many of the other most significant sets relate to lipids and immunity.
Conclusions
The EADB project allowed us to identify several new associated loci for AD, including several candidate genes linked to amyloid precursor protein metabolism or that are likely to be involved in AD-related microglia dysfunctions, and loci already associated with the risk of developing other neurodegenerative diseases. Additional insights into the genetics of AD are expected from other ongoing analyses.