Retromer dysfunction in amyotrophic lateral sclerosis
Eduardo Pérez-Torres, Irina Utkina-Sosunova, Vartika Mishra, Peter A. Barbuti, Mariangels De Planell-Saguer, Georgia Dermentzaki, Heather Geiger, Anna O. Basile, Nicolas Robine, Delphine Fagegaltier, Kristin A. Politi, Paola Rinchetti, Vernice Jackson‐Lewis, Matthew Harms, Hemali Phatnani, Francesco Lotti, Serge Przedborski, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B. Lee, Vivianna M. Van Deerlin, Neil A. Shneider, Ernest Fraenkel, Lyle W. Ostrow, Frank Baas, Noah Zaitlen, James D. Berry, Andrea Malaspina, Pietro Fratta, Gregory A. Cox, Leslie M. Thompson, Steven Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman‐Patterson, Molly Hammell, Nikolaos A. Patsopoulos, Oleg Butovsky, Josh Dubnau, Avindra Nath, Robert Bowser, Matthew Harms, Eleonora Aronica, Mary Poss, Jennifer E. Phillips‐Cremins, John F. Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Robert H. Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent T. Harris, Iris Broce, Vivian E. Drory, John Ravits, Corey T. McMillan, Vilas Menon, Lani F. Wu, Steven J. Altschuler, Yossef Lerner, Rita Sattler, Kendall Van Keuren‐Jensen, Orit Rozenblatt–Rosen, Kerstin Lindblad‐Toh, Katharine Nicholson, Peter K. Gregersen, Jeong‐Ho Lee, Maze Therapeutics, Bristol-Myers Squibb, Pfizer, Sulev Kokos, Stephen Muljo, Bryan J. Traynor
Abstract
Retromer is a heteropentameric complex that plays a specialized role in endosomal protein sorting and trafficking. Here, we report a reduction in the retromer proteins—vacuolar protein sorting 35 (VPS35), VPS26A, and VPS29—in patients with amyotrophic lateral sclerosis (ALS) and in the ALS model provided by transgenic (Tg) mice expressing the mutant superoxide dismutase-1 G93A. These changes are accompanied by a reduction of levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA1, a proxy of retromer function, in spinal cords from Tg SOD1 G93A mice. Correction of the retromer deficit by a viral vector expressing VPS35 exacerbates the paralytic phenotype in Tg SOD1 G93A mice. Conversely, lowering Vps35 levels in Tg SOD1 G93A mice ameliorates the disease phenotype. In light of these findings, we propose that mild alterations in retromer inversely modulate neurodegeneration propensity in ALS.