Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia - PubMed
4 hours ago
- #TMEM106B fragment
- #frontotemporal dementia
- #granulin deficiency
- Frontotemporal dementia (FTD) is the second most common dementia after Alzheimer's disease, with GRN mutations being a major cause.
- TMEM106B genetic variants modify FTD risk, especially in GRN mutation carriers, and protective haplotypes can offer near lifetime protection.
- A C-terminal fragment of TMEM106B forms amyloid fibrils and accumulates in neurodegenerative disorders, including FTD.
- Granulin deficiency leads to accumulation of the TMEM106B C-terminal fragment in lysosomes in knockout mice and human iPSC-derived neurons.
- Progranulin supplementation reduces fragment accumulation, and TMEM106B risk alleles show allele-dose-dependent increases in fragments, reversible by progranulin.
- TMEM106B dimerization stabilizes the protein and limits fragment formation, linking granulin deficiency to fragment accumulation and explaining TMEM106B's role in FTD risk and protection.