CLUC CLUT DNA binding proteins

ABSTRACT: Alzheimers disease (AD) is the most common form of dementia in the elderly with no cure. Although huge efforts have been made to develop drugs for AD, most programs aimed for disease-modifying therapies have failed. Possible reasons for the high failure rate include insufficient understanding of mechanisms underlying AD pathogenesis. The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset AD. However, whether the CLU rs11136000 SNP is functional and what are molecular mechanisms underlying the risk effect of the CLU variant remain unknown. In this study, we identified the CLU rs11136000 SNP as a functional variant by CRIPSR/Cas9 knockout of the SNP. Moreover, by switching the risk C and the protective T alleles using CRISPR/Cas9 editing, we generated isogenic iPSCs with different alleles of the CLU rs11136000 SNP. Astrocytes derived from isogenic iPSCs carrying the C or T allele exhibited different CLU expression and differential inflammatory response. C/C astrocytes carrying two C alleles expressed higher level of CLU and exhibited elevated interferon (IFN) response and CXCL10 expression upon TNFalpha/IL1beta treatment. Furthermore, using human iPSC-derived astrocytes and OPCs co-cultured on nanofibers, we demonstrated that elevated CXCL10 expression in C/C astrocytes induced by TNFalpha/IL1beta led to inhibition of OPC proliferation and myelination. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk C allele carriers. This knowledge could help us to design more effective strategies to treat AD by targeting IFN response and CXCL10 that are upstream of myelination deficits, an early event in AD pathogenesis that proceeds before cognitive decline.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Yanhong Shi  

PROVIDER: MSV000088660 | MassIVE | Fri Jan 07 15:03:00 GMT 2022

SECONDARY ACCESSION(S): PXD030830

REPOSITORIES: MassIVE