The findings build on a 2006 discovery by co-senior authors Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, and John Q. Trojanowski, MD, PhD, director of the Institute of Aging at Penn. They led an international team that found that a protein called TDP-43 accumulates abnormally in brain tissue from individuals with one type of heritable FTLD. TDP-43 is a known protein widely expressed throughout the body, with multiple functions, including regulating transcription of the genetic code and as scaffolding for nuclear and motor neuron proteins.

FTLD cases that are characterized by TDP-43 inclusions can be passed from one generation to the next, as a result of mutations in another protein called progranulin (GRN). Using post-mortem brain tissue from 515 patients with TDP-associated FTLD, the team found that these patients had multiple genetic variations called SNPs in common in a region on chromosome 7 containing the protein TMEM106B, compared to over 2,500 disease-free controls.

From this, the team concluded that the TMEM106B gene variants confer a higher genetic risk for all FTLD-TDP patients, as well as in the subset of patients with GRN mutations. What's more, alterations in levels of TMEM106B protein in the brain may be directly or indirectly involved in causing FTLD.

How TDP-43, GRN, and TMEM106B proteins might normally interact in brain cells and be disrupted in FTLD remains to be deciphered. Nevertheless, the discovery of TMEM106B is an important step toward a better understanding of FTLD. The team plans to sequence the TMEM106B segment of chromosome 7, and in parallel, study the normal functions of TMEM106B.

Patrick M.A. Sleiman, PhD in the Center for Applied Genomics at CHOP; Maria Martinez-Lage, MD, postdoctoral fellow in Pathology and Laboratory Medicine; and Alice Chen-Plotkin, MD, Instructor in the Department of Neurology, both at Penn, along with Van Deerlin, are co-first authors on the Nature Genetics article. Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP is also a senior author on the paper. Other Penn co-authors are Li-San Wang, PhD; Gerard D. Schellenberg, PhD; Murray Grossman, MD, and Steven Arnold, MD.

The Penn authors have submitted a patent application for TMEM106B.
This study was funded in part by the National Institute on Aging.