Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes
Summary
Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation. Copyright © 2024 University of California San Diego. Published by Elsevier Inc. All rights reserved.
| Authors | Al-Azzam N, To JH, Gautam V, Street LA, Nguyen CB, Naritomi JT, Lam DC, Madrigal AA, Lee B, Jin W, Avina A, Mizrahi O, Mueller JR, Ford W, Schiavon CR, Rebollo E, Vu AQ, Blue SM, Madakamutil YL, Manor U, Rothstein JD, Coyne AN, Jovanovic M, Yeo GW |
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| Journal | Neuron |
| Publication Date | 2024 Dec 18;112(24):4033-4047.e8 |
| PubMed | 39486415 |
| PubMed Central | PMC12380415 |
| DOI | 10.1016/j.neuron.2024.10.007 |