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Research sheds light on genetics of FTLD-TDP risk and progression

May 23, 2024

Genetic variation at the transmembrane protein 106B (TMEM106B) gene has been known to modify disease risk and progression in frontotemporal lobar dementia with TDP-43 protein (FTLD-TDP). However, the mechanism is unelucidated.

Mayo Clinic researchers have found that a minor TMEM106B allele is associated with longer survival at disease outset. The researchers also found an association between a major TMEM106B allele and more-aggressive disease progression, with accumulation of TMEM106B-derived filaments. The findings were published in Science Translational Medicine.

Efforts to explore connections between TMEM106B mutations and FTLD-TDP progression have been hindered by the lack of antibodies for detecting the TMEM106B core filament sequence. The Mayo Clinic researchers developed such an antibody and used it to examine postmortem brain tissue from individuals with confirmed FTLD-TDP and confirmed TMEM106B pathology.

More than 250 samples from the Mayo Clinic Brain Bank were analyzed.

Key findings:

  • The TMEM106B major allele was associated with higher core accumulation in patients with FTLD-TDP.
  • Minimal core deposition was detected in carriers of the minor allele.
  • Increased core deposition was associated with enhanced TDP-43 dysfunction.
  • Interactome data suggest a role for TMEM106B filaments in impaired RNA transport, local translation and endolysosomal function in FTLD-TDP.

Overall, the findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective allele reduces disease risk and slows progression.

"Our research provides evidence that genetic variants in TMEM106B are an essential factor to consider in study groups of patients with FTD," says Casey N. Cook, Ph.D., a neuroscientist at Mayo Clinic in Jacksonville, Florida. "The work also suggests that novel therapeutic interventions to prevent the buildup of the tangled fiberlike structures might one day reduce disease risk or slow disease progression."

For more information

Marks JD, et al. TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Science Translational Medicine. 2024;16:eadf9735.

Refer a patient to Mayo Clinic.