In a study published earlier this year in the journal Science Translational Medicine, researchers from Mayo Clinic share their discovery of the ways inherited variations in a specific gene can influence the risk and severity of FTD.

People who have an inherited genetic variant in the GRN gene must contend with a significantly elevated risk of developing FTD caused by TDP-43. However, previous research has shown that if or when FTD symptoms develop is influenced by inherited variants in the TMEM106B gene, which encodes transmembrane protein 106B, which helps maintain a healthy lysosome. As highlighted in an Alzforum post, researchers previously discovered that a different, rare inherited variant of TMEM106B appeared to delay FTD onset and slow its progression. While TMEM106B variants had been known to create protein filaments and fibrils, exactly how these genetic variants influenced the severity and progression of FTD has not been understood until the recent Mayo Clinic study.

The researchers began by investigating how the different variants affected people with FTD. They analyzed 228 brains donated by people with FTD caused by TDP-43, finding that the 18 people who were found to have the protective variant lived for longer than the 210 people with the risk-creating variant.

Then the researchers developed an antibody strain that would interact with a stretch of amino acids from the protein fibrils created by TMEM106B variants. When analyzing the results, the team found that the antibody labeled amino acid stretches believed to be associated with TMEM106B. The fibrils were abundant in people carrying the increased risk variant of TMEM106B, but hardly detectable in people with the protective TMEM106B variant and people without an FTD-causing variant. The team discovered a correlation between the abundance of fibrils and the aggregation of TDP-43.

Delving deeper into the interaction between other proteins and those originating from TMEM106B variants, the researchers discovered that the fibrils created by TMEM106B contained not only TDP-43 but also proteins involved in different cellular functions, and some associated with other neurodegenerative disorders.

These findings suggest that aggregation of proteins linked to TMEM106B variants somehow exacerbates the accumulation of TDP-43 and disrupts its role in regulating different cellular functions, providing a potential explanation for why the protective variant delays progression, the study’s authors write. Their findings also show that proteins created by TMEM106B variants appeared to interfere with other proteins.

Study co-author Leonard Petrucelli, PhD, received an FTD Biomarkers Initiative grant in 2018 for his research evaluating poly(GP) proteins as a biomarker for FTD caused by c9orf72 variants.

C9orf72, GRN, and MAPT are just some of the genes associated with FTD, and researchers continue to discover new genes that can create a risk for FTD. If you are concerned about your genetic risk for FTD, genetic testing can identify risk-creating genetic variants. AFTD strongly recommends genetic counseling as a first step to consider if genetic testing is right for you.