Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Alice Chen-Plotkin


Frontotemporal lobar degeneration (FTLD) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association (GWAS) to confer genetic risk for FTLD-TDP, the largest neuropathological subset of FTLD (p=1x10-11, OR=1.6). Prior to its discovery in the GWAS, TMEM106B, or Transmembrane Protein 106B, was uncharacterized. To further understand the role of TMEM106B in disease pathogenesis, we used immortalized as well as primary neurons to assess the cell biological effects of disease-relevant levels of TMEM106B overexpression and the interaction of TMEM106B with additional disease-associated proteins. We also employed immunostaining to assess its expression pattern in human brain from controls and FTLD cases.

We discovered that TMEM106B is a highly glycosylated, Type II late endosomal/lysosomal transmembrane protein. We found that it is expressed by neurons, glia, and peri-vascular cells in disease-affected and unaffected regions of human brain from normal controls in a cytoplasmic, perikaryal distribution. In brain from FTLD patients, we discovered a striking loss of subcellular localization with highly disordered TMEM106B immunostaining patterns in a subset of FTLD-TDP cases. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing TMEM106B mRNA and protein expression levels. We therefore investigated the cell biological effects of increased TMEM106B expression. Increased TMEM106B results in a decrease in the average number of late endosomes/lysosomes per cell, loss of lysosomal acidification, and impaired lysosomal degradation. In addition, lysosomal deficits are accompanied by the appearance of enlarged organelles (>2-3μm) demonstrating ultrastructural characteristics of late autophagic vacuoles (autolysosomes/amphisomes). We observed these effects in both immortalized cell lines and in primary neurons overexpressing TMEM106B. Furthermore, we show that the effects of increased TMEM106B expression can be abrogated by (1) a single point mutation to a lysosomal sorting motif in TMEM106B newly identified here, or (2) knockdown of C9orf72 protein. In sum, our results suggest that TMEM106B exerts its effects on FTLD-TDP disease risk through alterations of lysosomal and autophagic pathways and that TMEM106B and C9orf72 may interact in disease pathophysiology.

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