Format

Send to

Choose Destination
Hum Mol Genet. 2019 Mar 1;28(5):718-735. doi: 10.1093/hmg/ddy376.

Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
2
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
3
Cell Circuits Program, Broad Institute, Cambridge, MA, USA.
4
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Abstract

Large-scale 'omic' studies investigating the pathophysiological processes that lead to Alzheimer's disease (AD) dementia have identified an increasing number of susceptibility genes, many of which are poorly characterized and have not previously been implicated in AD. Here, we evaluated the utility of human induced pluripotent stem cell-derived neurons and astrocytes as tools to systematically test AD-relevant cellular phenotypes following perturbation of candidate genes identified by genome-wide studies. Lentiviral-mediated delivery of shRNAs was used to modulate expression of 66 genes in astrocytes and 52 genes in induced neurons. Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-β (Aβ) levels. Knockdown of AP3M2, CNN2, GSTP1, NPC1, NPC2, PSAP and SORL1 reduced interleukin-6 levels in astrocytes. Only knockdown of FERMT2 led to a reduction in the proportion of TAU that is phosphorylated. Further, CRISPR-Cas9 targeting of FERMT2 in both familial AD (fAD) and fAD-corrected human neurons validated the findings of reduced extracellular Aβ. Interestingly, FERMT2 reduction had no effect on the Aβ42:40 ratio in corrected neurons and a reduction of phospho-tau, but resulted in an elevation in Aβ42:40 ratio and no reduction in phospho-tau in fAD neurons. Taken together, this study has prioritized 15 genes as being involved in contributing to Aβ accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.

PMID:
30371777
PMCID:
PMC6381320
DOI:
10.1093/hmg/ddy376

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center