To the end of the line: Axonal mRNA transport and local translation in health and neurodegenerative disease

Costa, Christopher J.; Willis, Dianna E.

doi:10.1002/dneu.22555

Cited by 59 publications

(52 citation statements)

References 101 publications

(125 reference statements)

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“…Several neurodegeneration-associated proteins are involved in mRNA export, trafficking, localization, and translation. These processes offer a plausible explanation for the unique pathogeneses observed in neurons, which have dendritic and axonal extremities requiring local translation and mRNA transport across distances vastly larger than the cell body (recently reviewed in [95–97]). The recent discovery that certain ribosomal subunits preferentially translate subsets of mRNA [98] provides an additional layer to the complex mosaic that is translation within neurons.…”

Section: Discussionmentioning

confidence: 99%

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lehmkuhl

Zarnescu

2018

Advances in Neurobiology

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Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease. Here, we review dysregulation of translation in the context of age-related neurodegeneration and discuss novel methods to interrogate translation. This review primarily focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum disorder heavily associated with RNA metabolism, while also analyzing translational inhibition in the context of related neurodegenerative disorders such as Alzheimer's disease and Huntington's disease and the translation-related pathomechanisms common in neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lehmkuhl

Zarnescu

2018

Advances in Neurobiology

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“…We refer to a number of recent excellent publications for a comprehensive review regarding the role of the 3′ and 5′ UTRs in mediating RNA localization ad gene expression in various cell types, including neurons (Holt and Schuman, 2013; Mayr, 2017; Costa and Willis, 2018; Sahoo et al, 2018). …”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional Processing of mRNA in Neurons: The Vestiges of the RNA World Drive Transcriptome Diversity

Andreassi

Crerar

Riccio

2018

Front. Mol. Neurosci.

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Neurons are morphologically complex cells that rely on the compartmentalization of protein expression to develop and maintain their extraordinary cytoarchitecture. This formidable task is achieved, at least in part, by targeting mRNA to subcellular compartments where they are rapidly translated. mRNA transcripts are the conveyor of genetic information from DNA to the translational machinery, however, they are also endowed with additional functions linked to both the coding sequence (open reading frame, or ORF) and the flanking 5′ and 3′ untranslated regions (UTRs), that may harbor coding-independent functions. In this review, we will highlight recent evidences supporting new coding-dependent and -independent functions of mRNA and discuss how nuclear and cytoplasmic post-transcriptional modifications of mRNA contribute to localization and translation in mammalian cells with specific emphasis on neurons. We also describe recently developed techniques that can be employed to study RNA dynamics at subcellular level in eukaryotic cells in developing and regenerating neurons.

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“…However, what mechanisms are responsible for CRMP4 elevation specifically in ALS is unknown. miRNA downregulation and defects in local protein synthesis are common features in several ALS models (Haramati et al ., 2010; Costa and Willis, 2018). Along with that, Sema3A was shown to induce axonal local synthesis in several neuronal systems (Campbell and Holt, 2001; Wu et al ., 2005; Manns et al ., 2012; Cagnetta et al ., 2018, 2019).…”

Section: Discussionmentioning

confidence: 99%

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Maimon

Ankol

Weissova

et al. 2019

Preprint

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29Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease 30 with selective dysfunction; it causes the death of motor neurons (MNs). In spite of 31 some progress, currently no effective treatment is available for ALS. Before such 32 treatment can be developed, a more thorough understanding of ALS pathogenesis is 33 required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS 34 pathology via secretion of destabilizing factors such as Sema3A; these factors trigger 35 axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on 36 the molecular mechanism by which muscle contribute to MNs loss in ALS. We 37 identified CRMP4 as part of a retrograde death signal generated in response to 38 muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A 39 induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1 G93A ) 40 and human-derived (C9orf72) ALS models. Introducing peptides that interfere with 41 CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN 42 loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN 43 loss in ALS. 44 45 46 Summary 47 Maimon et al. identify a novel retrograde death mechanism that contribute to MN loss 48 in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the 49 axon.50 51 52 53 105 Strittmatter, 2007). The canonical signaling events of CRMPs during Semaphorin 106 signaling involve their phosphorylation via GTPase activity, which further leads to 107 microtubule destabilization and axon retraction (Sasaki et al., 2002; Yamashita and 108 5 Goshima , 2012; Balastik et al., 2015). In addition to their role in mediating Sema3A 109 intrinsic responses, CRMPs were also reported to bind dynein and kinesin, and 110 modulate their function (Arimura et al., 2009; Rahajeng et al., 2010). Several studies 111 further demonstrated the involvement of CRMPs in neurodegenerative diseases 112 (Charrier et al., 2003; Yamashita and Goshima, 2012; Nagai, Baba and Ohshima, 113 2017). Specifically, CRMP4 expression levels were previously found to be elevated in 114 the SOD1 G93A mouse spinal cord, and were suggested to hamper MN health (Duplan 115 et al., 2010; Valdez et al., 2012; Nagai et al., 2015). However, the mechanism underline 116 the involvement of CRMP4 mediating cell death and its role in other ALS model is still 117 elusive. Moreover, mutations in CRMP4 were associated with ALS patients (Blasco et 118 al., 2013). 119 120 Here, we identified a novel retrograde death signal, triggered by Sema3A, which 121 facilitates MN loss in both murine and human ALS models. This process is mediated 122 by the formation of CRMP4-Dynein complex along diseased axons. Interfering with the 123 binding of CRMP4 to Dynein by using short blocking peptides rescues Sema3A-124 dependent MN loss in these ALS models. 125 126 Results 127 128 SOD G93A MNs and muscle co-cultures enhance MN loss 129 MN cell death is a key process in ALS pathology. Taking into consideratio...

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To the end of the line: Axonal mRNA transport and local translation in health and neurodegenerative disease

Cited by 59 publications

References 101 publications

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Post-transcriptional Processing of mRNA in Neurons: The Vestiges of the RNA World Drive Transcriptome Diversity

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

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