Retromer dysfunction in amyotrophic lateral sclerosis
Author(s)
Fraenkel, Ernest
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<jats:p>
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
<jats:sup>G93A</jats:sup>
mice. Correction of the retromer deficit by a viral vector expressing
<jats:italic>VPS35</jats:italic>
exacerbates the paralytic phenotype in Tg SOD1
<jats:sup>G93A</jats:sup>
mice. Conversely, lowering
<jats:italic>Vps35</jats:italic>
levels in Tg SOD1
<jats:sup>G93A</jats:sup>
mice ameliorates the disease phenotype. In light of these findings, we propose that mild alterations in retromer inversely modulate neurodegeneration propensity in ALS.
</jats:p>
Date issued
2022Department
Massachusetts Institute of Technology. Department of Biological EngineeringJournal
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