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Unraveling RNA-Binding Protein Mislocalization in Neurodegenerative Disorders

Abstract

Mislocalization of RNA-binding proteins (RBPs) is a hallmark of neurodegenerative diseases like ALS, where the abnormal distribution of RBPs disrupts cellular functions. TDP-43, typically found in the nucleus, accumulates in cytoplasmic inclusions in ALS neurons, impairing RNA metabolism and leading to neurodegeneration. ALS is also linked to reduced nucleoporins and increased nuclear CHMP7, a protein that damages nuclear pores. Using CRaft-ID, we identified 55 RBPs that affect CHMP7 localization, focusing on SmD1, a component of the SMN complex. We found that CHMP7 interacts with SmD1 and related proteins in an RNA-sensitive manner and observed reduced SmD1 in ALS iPSC-derived motor neurons (MNs). Inhibiting SmD1/SMN increased nuclear CHMP7, while overexpressing SmD1 restored CHMP7 localization and STMN2 splicing. These findings highlight early ALS pathogenesis driven by SMN complex dysregulation.

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