Retromer dysfunction in amyotrophic lateral sclerosis
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pnas.2118755119.pdf
Description
Published version
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1.96 MB
Format
Adobe PDF
Checksum (MD5)
15fb946638e9007df0f819e4373a8321
Author(s)
Fraenkel, Ernest
Date Issued
2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Citation
Fraenkel, Ernest. 2022. "Retromer dysfunction in amyotrophic lateral sclerosis." Proceedings of the National Academy of Sciences of the United States of America, 119 (26).
Version
Final published version
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.
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1073/PNAS.2118755119
