CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy

Transport and local translation of mRNAs in distal axonal compartments are essential for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects mitochondria from damage during their long journey along the axon, however the regulatory factors involved are largely unkno...

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Published inbioRxiv
Main Authors Zaninello, Marta, Schlegel, Tim, Nolte, Hendrik, Pirzada Mujeeb Ur Rehman, Savino, Elisa, Barth, Esther, Wuestenberg, Hauke, Uddin, Tesmin, Wolff, Lisa, Wirth, Brunhilde, Lehmann, Helmar, Cioni, Jean-Michel, Langer, Thomas, Rugarli, Elena
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.12.2023
Subjects
Axon guidance
Mitochondria
Motor neurons
Neurodegeneration
Peripheral neuropathy
Proteins
Quality control
Recycling
Ribonucleic acid
Ribosomal subunits
RNA
Translation initiation
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Summary:Transport and local translation of mRNAs in distal axonal compartments are essential for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects mitochondria from damage during their long journey along the axon, however the regulatory factors involved are largely unknown. Here, we show that CLUH, a cytosolic protein that binds mRNAs encoding mitochondrial proteins, is essential for preventing axonal degeneration of spinal motoneurons and maintaining motor behavior in the mouse. We demonstrate that CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The absence of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits specifically in the growth cone. CLUH binds ribosomal subunits, translation initiation and ribosome recycling components, and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the growth cone and translation defects in CLUH-deficient motoneurons. In conclusion, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which are essential for their development and long-term integrity and function.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2023.12.02.569712