TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models

Nov 1, 2023·
Sara L Dominguez
,
Benjamin I Laufer
,
Arundhati Sengupta Ghosh
,
Qingling Li
,
Gaia Ruggeri
,
Maheswara Reddy Emani
,
Lilian Phu
,
Brad a Friedman
,
Wendy Sandoval
,
Christopher M Rose
,
Hai Ngu
,
Oded Foreman
,
Mike Reichelt
,
Yves Juste
,
Guita Lalehzadeh
,
Dennis Hansen
,
Helle Nymark
,
Denia Mellal
,
Helene Gylling
,
Łukasz J Kiełpiʼnski
,
Ben Chih
,
Baris Bingol
,
Casper C Hoogenraad
,
William J Meilandt
,
Amy Easton
· 0 min read
DOI
Abstract
Heterozygous mutations in the granulin (GRN) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. TMEM106B deletion did not reverse transcriptomic or proteomic profiles in GRN-deficient microglia, with a few exceptions in immune signaling markers. Neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated phenotypes in Grn -/-mice. Furthermore, Tmem106b reduction by antisense oligonucleotide (ASO) was poorly tolerated in Grn -/-mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTD-GRN.
Type
Publication
iScience