Newswise — PHILADELPHIA – Seven years ago, Penn Medicine researchers showed that mutations in the TMEM106B gene significantly increased a person’s risk of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in those under 65. While the data confirmed the gene’s clinical relevance, it didn’t tell researchers how it caused the disease – which is vital to developing new therapeutics.

Now, a new study published online this week in the American Journal of Human Genetics from Penn researchers helps answer that question by uncovering the mechanisms of the genetic mutations, or variants, associated with the gene. By functionally dissecting the TMEM106B gene first linked to FTLD, the researchers have shown how its variants directly affect the architecture and expression of it, and thus how it may lead to disease.

This is among the first functional studies of gene variants known to be associated with neurodegenerative diseases.

“Approximately 200 variants linked to these diseases -- Alzheimer’s, Parkinson’s, FTLD, ALS -- have been discovered, but how they actually influence them is not fully understood,” said senior author Alice S. Chen-Plotkin, MD, an associate professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania. “In general, more functional studies like this one need to be conducted downstream of the genes, so we can get to the root of the problem. Otherwise, what’s the point of finding variants? We need to determine what they mean in a biological sense in order to find targetable pathways.”

FTLD is characterized by the progressive loss of neurons in the frontal and temporal regions of the brain. It affects approximately 15 people out of 100,000 between the ages of 45 and 64. It is a fatal disease with death typically occurring within eight years of diagnosis. As is the case with all neurodegenerative diseases, there are no disease-modifying therapies available today to treat FTLD.

Through a combination of data-mining of publicly available databases of genetic information and laboratory studies using multiple tissue types, such as neurons and white blood cells, the researchers confirmed that the genetic variants known to increase a patient’s risk of FTLD correlated with an increased expression of TMEM106B. And that it depended on whether cells recruited more CTCF or less CTCF, a key protein that helps dictate and organize the structure of the genome. A “causal’ variant known as rs1990620 was responsible for recruiting CTCF, the authors found.

That variant attracted more CTCF to the cells, which translated into more long-range interactions, particularly between the promoters and the enhancers, the researchers found. The promotor is a region of DNA that starts the transcription of a particular gene, while an enhancer helps close the deal.

Those long-range interactions are what led to the increased levels of TMEM106B in the cells, the study suggests, which then caused abnormal lysosome activity and cellular toxicity. The “trash cans” of those cells essentially became out of order.

“If you are a cell, you only have two ways to get rid of junk: your proteasomes and lysosomes. If one of those trash cans doesn’t work as well, especially if you are a neuron, it can cause problems,” Chen-Plotkin said. “Neurons can’t just die and renew. They have super long processes that they need to regulate themselves. This break down may be what ultimately puts people on the path toward neurodegeneration.”

Researchers at Penn will continue to drill down even further into the TMEM106B gene to better understand the downstream cell biology, Chen-Plotkin said. The team also plans to further investigate other variants associated with neurodegenerative diseases. Too few functional studies, she said, have been initiated, not only in neurology, but also in all disease types.

“This type of approach can be applied to the other 199 or so neurodegenerative disease risk loci,” she said. “Given that so much investment has already been made to identify them, we want to derive the maximum biological meaning from them, because we may hit a pathway that is very meaningful and really targetable.”

Co-authors on the study include Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, and Christopher D. Brown.

The study was funded by in part by the National Institutes of Health (R01 NS082265, U01 HL129998, R01 MH101822, and F31 NS090892) and the Burroughs Wellcome Fund.


Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.