Progranulin and TMEM106B: when two become wan.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Mutations in the GRN gene, encoding progranulin, are a primary cause of familial frontotemporal dementia (FTD).
• TMEM106B is a known risk factor for GRN-mutation-associated FTD, and both proteins are crucial for lysosome function.
• Previous studies suggested that elevated TMEM106B levels increase FTD risk, prompting investigation into TMEM106B reduction as a therapeutic strategy.

Purpose of the Study:

• To investigate the therapeutic potential of reducing TMEM106B levels in the context of GRN-related FTD.
• To examine the consequences of complete TMEM106B deficiency in mice with GRN mutations.

Main Methods:

• Generation and analysis of Grn knockout mice crossed with Tmem106b knockout mice.
• Assessment of FTD-related behavioral defects, lysosome dysfunction, neurodegeneration, and TDP-43 pathology.

Main Results:

• Complete removal of Tmem106b in Grn knockout mice exacerbated FTD phenotypes, including severe motor deficits and neurodegeneration.
• Lysosome abnormalities and gliosis were enhanced in double knockout mice.
• TDP-43 pathology, a hallmark of human FTD with GRN mutations, developed in the double knockout mice, which was not consistently observed in single knockouts.

Conclusions:

• Reducing TMEM106B levels is not a viable therapeutic strategy for FTD caused by GRN mutations and may worsen disease.
• These findings challenge the notion that TMEM106B reduction is beneficial and suggest a complex role for TMEM106B in FTD pathogenesis.
• The results necessitate a re-evaluation of TMEM106B's function and its potential as a therapeutic target in FTD.