mRNA stability and m6A are major determinants of subcellular mRNA localization in neurons

Loedige, Inga; Baranovskii, Artem; Mendonsa, Samantha; Dantsuji, Sayaka; Popitsch, Niko; Breimann, Laura; Zerna, Nadja; Черепанов, В. М.; Milek, Miha; Ameres, Stefan L.; Chekulaeva, Marina

doi:10.1016/j.molcel.2023.06.021

Cited by 32 publications

(11 citation statements)

References 82 publications

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“…In further agreement with our conclusion is the observation of a decreased axonal abundance of the Pink1 mRNA, which is known to be transported via binding to synaptojanin 2 and synaptojanin 2 binding protein ( 5 ). The stability of mRNAs is per se an important determinant of neurite localization ( 44 ). Notably, CLUH target mRNAs are depleted of destabilizing factors, increasing the likelihood that they reach the peripheral regions of a neuron ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

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

Zaninello,

Schlegel,

Nolte

et al. 2024

Sci. Adv.

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Transporting and translating mRNAs in axons is crucial for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects long-lived axonal mitochondria from damage; however, the regulatory factors involved are largely unknown. We show that CLUH, which binds mRNAs encoding mitochondrial proteins, prevents peripheral neuropathy and motor deficits in the mouse. CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The lack of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits in the growth cone. CLUH interacts with ribosomal subunits, translation initiation, and ribosome recycling components and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the mRNA and translation defects, as well as the growth cone size, in CLUH-deficient motoneurons. Thus, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which is essential for their development and long-term integrity and function.

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Section: Discussionmentioning

confidence: 99%

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

Zaninello,

Schlegel,

Nolte

et al. 2024

Sci. Adv.

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“…The stability of mRNAs is per se an important determinant of neurite localization. Indeed, CLUH target mRNAs are depleted of destabilizing factors that render less likely that an mRNA reaches the peripheral regions of a neuron ( 39 ). 207 out of 229 putative CLUH targets contain less than 9 A-U rich elements in the 3’ UTR and only 26 out 229 are m 6 A ( N 6 -methyladenosine)-enriched ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, CLUH target mRNAs are depleted of destabilizing factors that render less likely that an mRNA reaches the peripheral regions of a neuron ( 39 ). 207 out of 229 putative CLUH targets contain less than 9 A-U rich elements in the 3’ UTR and only 26 out 229 are m 6 A ( N 6 -methyladenosine)-enriched ( 39 ). Since we previously showed that the targets are subjected to faster decay in absence of CLUH in cellular models ( 16, 19 ), one supposition is that CLUH acts as a stabilizing factor during the mRNA life cycle.…”

Section: Discussionmentioning

confidence: 99%

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

Zaninello,

Schlegel,

Nolte

et al. 2023

Preprint

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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.

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“…Interestingly, a recent study showed that mRNA stability is a major determinant of mRNA localization in neurons, with more stable transcripts being enriched in neurites ( Loedige et al, 2023 ). The authors reported that neurite-enriched RNAs have lower levels of m 6 A, and they found that disrupting m 6 A or other factors that control RNA stability promotes neurite enrichment of neuronal transcripts.…”

Section: A Function and Regulation In The Brainmentioning

confidence: 99%

Studying m6A in the brain: a perspective on current methods, challenges, and future directions

Tegowski,

Meyer

2024

Front. Mol. Neurosci.

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A major mechanism of post-transcriptional RNA regulation in cells is the addition of chemical modifications to RNA nucleosides, which contributes to nearly every aspect of the RNA life cycle. N6-methyladenosine (m6A) is a highly prevalent modification in cellular mRNAs and non-coding RNAs, and it plays important roles in the control of gene expression and cellular function. Within the brain, proper regulation of m6A is critical for neurodevelopment, learning and memory, and the response to injury, and m6A dysregulation has been implicated in a variety of neurological disorders. Thus, understanding m6A and how it is regulated in the brain is important for uncovering its roles in brain function and potentially identifying novel therapeutic pathways for human disease. Much of our knowledge of m6A has been driven by technical advances in the ability to map and quantify m6A sites. Here, we review current technologies for characterizing m6A and highlight emerging methods. We discuss the advantages and limitations of current tools as well as major challenges going forward, and we provide our perspective on how continued developments in this area can propel our understanding of m6A in the brain and its role in brain disease.

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mRNA stability and m6A are major determinants of subcellular mRNA localization in neurons

Cited by 32 publications

References 82 publications

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

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

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

Studying m6A in the brain: a perspective on current methods, challenges, and future directions

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