| Literature DB >> 35749364 |
Eduardo J Pérez-Torres1,2, Irina Utkina-Sosunova2,3, Vartika Mishra1,2, Peter Barbuti2,3, Mariangels De Planell-Saguer1,2, Georgia Dermentzaki1,2, Heather Geiger4, Anna O Basile4, Nicolas Robine4, Delphine Fagegaltier5, Kristin A Politi1,2, Paola Rinchetti1,2, Vernice Jackson-Lewis1,2,3, Matthew Harms3,6, Hemali Phatnani2,3,5, Francesco Lotti1,2, Serge Przedborski1,2,3,7.
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 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.Entities:
Keywords: ALS; neurodegeneration; retromer
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Year: 2022 PMID： 35749364 PMCID： PMC9245686 DOI： 10.1073/pnas.2118755119
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 12.779