Identification and characterization of frontotemporal dementia risk factor TMEM106B interacting proteins

Identification: Charan, Rakshita


Description

Identification and characterization of frontotemporal dementia risk factor TMEM106B interacting proteins
 
Rakshita A. Charan1, Travis L. Unger1, Defne Amado1, Alice S. Chen-Plotkin1
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, USA
 
Frontotemporal lobar degeneration (FTLD) is one of the leading causes of early-onset dementia, but the pathological mechanisms underlying this disorder are not very well understood. Common variants at the gene encoding Transmembrane Protein 106B (TMEM106B) have been shown to increase genetic risk for FTLD with TAR DNA-binding Protein 43 (TDP-43) inclusions (FTLD-TDP-43), with variants associated with increased TMEM106B expression also associating with greater disease risk. We have previously demonstrated that TMEM106B localizes to endosomes/lysosomes, and disease-associated-increases of TMEM106B expression result in lysosomal abnormalities and accumulation of enlarged vacuoles in various cell types, including neurons. In the present study, we sought to understand the molecular mechanisms underlying these cellular phenotypes by identifying the interacting partners of TMEM106B. Using immunoprecipitation in combination with mass spectrometry (IP-MS), we identified 329 proteins that interact with TMEM106B in HEK293 cells. Pathway analysis suggested enrichment in proteins involved in the SNARE complex, and the vesicle-associated membrane protein 8 (VAMP8), a SNARE protein known to play a role in lysosomal and autophagosome function, was verified to interact with TMEM106B.  Finally, knockdown of VAMP8 rescues multiple abnormalities induced by TMEM106B over-expression, suggesting that VAMP8 and TMEM106B may function in the same pathways in cellular health and disease.  
 

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