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 SOD1G93A mice. Correction of the retromer deficit by a viral vector expressing VPS35 exacerbates the paralytic phenotype in Tg SOD1G93A mice. Conversely, lowering Vps35 levels in Tg SOD1G93A mice ameliorates the disease phenotype. In light of these findings, we propose that mild alterations in retromer inversely modulate neurodegeneration propensity in ALS.
PNAS June 24, 2022 119 (26) e2118755119 https://doi.org/10.1073/pnas.2118755119
Eduardo J. Perez-Torres , Irina Utkina-Sosunova , Vartika Mishra , Peter Barbuti , Mariangels De Planell-Saguer , Georgia Dermentzaki , Heather Geiger , Anna O. Basile , Nicolas Robine , Delphine Fagegaltier , Kristin A. Politi , Paola Rinchetti , Vernice Jackson-Lewis , NYGC ALS Consortium , Matthew Harms , Hemali Phatnani , Francesco Lotti , and Serge Przedborski
Author affiliations: a Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032; b Center for Motor Neuron Biology and Diseases, Columbia University Irving Medical Center, New York, NY 10032; c Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032; d Computational Biology, New York Genome Center, New York, NY 10013; e Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013; f Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032; and g Department of Neuroscience, Columbia University, New York, NY 10027
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