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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Heterozygous granulin (GRN) gene mutations are a primary cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP).
• TMEM106B gene polymorphisms are linked to FTLD-TDP risk in GRN mutation carriers, with protective variants associated with lower TMEM106B levels.

Purpose of the Study:

• To investigate the therapeutic potential of reducing TMEM106B levels in GRN-deficient models of FTLD-TDP.
• To assess the impact of TMEM106B deletion or reduction on cellular and animal models of GRN deficiency.

Main Methods:

• Utilized mouse models with complete TMEM106B deletion and induced pluripotent stem cell (iPSC)-derived human microglia from GRN-deficient individuals.
• Analyzed transcriptomic and proteomic profiles, immune signaling markers, and disease-associated phenotypes in GRN-deficient models.
• Administered antisense oligonucleotides (ASOs) to reduce TMEM106B levels in GRN-deficient mice.

Main Results:

• TMEM106B deletion did not reverse transcriptomic or proteomic changes in GRN-deficient microglia, except for minor alterations in immune signaling.
• Neither homozygous nor heterozygous TMEM106B deletion normalized disease phenotypes in GRN-deficient mice.
• TMEM106B reduction using ASOs was poorly tolerated in GRN-deficient mice, indicating potential toxicity.

Conclusions:

• The study provides new insights into the roles of TMEM106B and GRN in microglial function.
• Reducing TMEM106B levels is not a supported therapeutic strategy for FTD-GRN, despite initial hypotheses based on genetic associations.