The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. (20th December 2013)

• Record Type: Journal Article
• Authors: Schwenk, Benjamin M; Lang, Christina M; Hogl, Sebastian; Tahirovic, Sabina; Orozco, Denise; Rentzsch, Kristin; Lichtenthaler, Stefan F; Hoogenraad, Casper C; Capell, Anja; Haass, Christian; Edbauer, Dieter
• Is Part Of: EMBO journal. Volume 33:Number 5(2014)
• Page Start: 450
• Page End: 467
• Publication Date: 2013-12-20
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.1002/embj.201385857
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="synopsis" xml:lang="en" id="embj201385857-abs-0002"> <title>Synopsis</title> <p> <boxed-text content-type="graphic" id="embj201385857-blkfxd-0001" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg4sxhd1cc" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> </p> <p>GWAS studies identified <italic>TMEM106B</italic> a major risk factor for frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology. This study combines loss‐off‐function experiments, live‐imaging and proteomics to elucidate the function of the lysosomal protein TMEM106B in neurons.</p> <p> <list id="embj201385857-list-0001" list-type="bullet"> <list-item> <p>Co‐immunoprecipitation experiments and mass‐spectrometry show that TMEM106B interacts with microtubule‐associated protein 6 (MAP6).</p> </list-item> <list-item> <p>TMEM106B knockdown promotes retrograde transport of dendritic lysosomes and dendrite loss, which is phenocopied by MAP6 overexpression.</p> </list-item> <list-item> <p>MAP6 knockdown rebalances dendritic trafficking of lysosomes and fully rescues the dendritic phenotype of TMEM106B knockdown.</p> </list-item> <list-item> <p>Promoting anterograde lysosomal transport using dominant negative Rab7‐interacting lysosomal protein (RILP) rescues dendrite loss in TMEM106B knockdown neurons.</p> </list-item> <list-item> <p>TMEM106B/MAP6 interaction controls dendritic branching, presumably by providing a molecular brake for retrograde dendritic trafficking of lysosomes.</p> </list-item> </list> </p> </abstract>