Although the first spinal muscular atrophy (SMA) therapy based on antisense oligonucleotides correcting SMN2 splicing has recently been approved, in type I SMA-affected individuals-representing 60% of SMA patients-the elevated survival motor neuron (SMN) level may still be insufficient to restore motor neuron function permanently. Plastin 3 (PLS3) and neurocalcin delta (NCALD) are two SMN-independent protective modifiers identified in humans and proved to be effective across various SMA animal models. Both PLS3 overexpression and NCALD downregulation protect against SMA by restoring impaired endocytosis; however, the exact mechanism of this protection is largely unknown. To unveil the mechanism behind the rescuing effect, the authors of the present study aimed to identify novel PLS3 interacting partners that could be used to modify the disease phenotype and as potential therapeutic targets. Here, they report the identification of calcineurin-like EF-hand protein 1 (CHP1) as a direct interacting partner of PLS3, show its protective effect in various in vitro and in vivo SMA models when it is downregulated, and unveil the molecular mechanism of protection underlying improved endocytosis.
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