Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Loss-of-function mutations in progranulin (GRN) are a primary cause of frontotemporal dementia (FTD).
• Progranulin deficiency leads to lysosomal dysfunction, observed as increased lysosomal proteins and lipofuscin accumulation in GRN mutation carriers.
• TMEM106B polymorphisms modify FTD risk in GRN mutation carriers, with higher TMEM106B levels associated with increased risk.

Purpose of the Study:

• To investigate whether partial reduction of TMEM106B can ameliorate social deficits and lysosomal abnormalities in Grn+/- mice, which model GRN-related FTD.
• To test the hypothesis that reducing TMEM106B levels protects against the pathogenic effects of progranulin haploinsufficiency.

Main Methods:

• Crossed Tmem106b+/- mice with Grn+/- mice to generate a combined heterozygous model.
• Assessed social behavior and lysosomal function, including specific enzyme activities, in the Grn+/- and Tmem106b+/-; Grn+/- mice.
• Quantified levels of lysosomal proteins and lipofuscin accumulation.

Main Results:

• Partial reduction of TMEM106B did not correct the age-dependent social deficits observed in Grn+/- mice.
• TMEM106B reduction failed to normalize most lysosomal abnormalities in Grn+/- mice.
• A notable exception was β-glucuronidase activity, which was normalized by TMEM106B reduction after being suppressed by TMEM106B reduction and increased by progranulin insufficiency.

Conclusions:

• The study's findings do not support the hypothesis that TMEM106B reduction is protective against progranulin haploinsufficiency.
• However, TMEM106B reduction demonstrated a capacity to normalize specific lysosomal phenotypes in Grn+/- mice, indicating a potential partial therapeutic role.
• Further research is needed to elucidate the complex interplay between TMEM106B and GRN in lysosomal function and neurodegeneration.