Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D

Regulation of intracellular traffic by TBK1 and its relevance to ALS

Neurons are highly polarised cells, typically comprising a somatodendritic compartment and an axon that can extend for a meter or more. Their extreme morphology challenges neurons to establish an efficient communication system between the axonal terminal and the soma, a mechanism known as axonal transport. Axonal transport is required for the maintenance of neuronal homeostasis, and is impaired in many neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). Mutations in TANK-binding kinase-1 (TBK1) have been described as causative for familial ALS. TBK1 phosphorylates Rab7, a small GTPase regulating the endolysosomal pathway. We have previously shown that the retrograde transport of signalling endosomes carrying neurotrophic receptors relies on Rab7, and that deficits in retrograde axonal transport can be detected at early symptomatic stages during ALS pathogenesis. In this work, we address whether TBK1 loss-of-function or Rab7-S72 phosphorylation alters the retrograde transport of signalling endosomes. We transfected Rab7 WT, S72A (phospho-deficient) and S72E (phospho-mimetic) in primary motor neurons and assessed the trafficking of signalling endosomes. Our results show that the directionality of transport is affected upon transfection of Rab7-S72E, whilst neuronal polarity remains unaltered. Axonal microtubule polarity also remains unchanged. We then characterised a set of shRNAs against TBK1 and showed that reduced TBK1 expression phenocopies the S72E condition. This alteration in transport is specific for signalling endosomes, as lysosomes and mitochondria were not affected. Altogether, these results suggest an involvement of TBK1 in the regulation of axonal transport of signalling endosomes and suggest that deficits in TBK1 activity determines retrograde transport dysfunction, which may be causative in ALS pathogenesis

The MAP1B case: An old MAP that is new again

© 2014 Wiley Periodicals, Inc. The functions of microtubule-associated protein 1B (MAP1B) have historically been linked to the development of the nervous system, based on its very early expression in neurons and glial cells. Moreover, mice in which MAP1B is genetically inactivated have been used extensively to show its role in axonal elongation, neuronal migration, and axonal guidance. In the last few years, it has become apparent that MAP1B has other cellular and molecular functions that are not related to its microtubule-stabilizing properties in the embryonic and adult brain. In this review, we present a systematic review of the canonical and novel functions of MAP1B and propose that, in addition to regulating the polymerization of microtubule and actin microfilaments, MAP1B also acts as a signaling protein involved in normal physiology and pathological conditions in the nervous system

Rab GTPase signaling in neurite outgrowth and axon specification

© 2016 Wiley Periodicals, Inc. Neurons are highly polarized cells that contain specialized subcellular domains involved in information transmission in the nervous system. Specifically, the somatodendritic compartment receives neuronal inputs while the axons convey information through the synapse. The establishment of asymmetric domains requires a specific delivery of components, including organelles, proteins, and membrane. The Rab family of small GTPases plays an essential role in membrane trafficking. Signaling cascades triggered by extrinsic and intrinsic factors tightly regulate Rab functions in cells, with Rab protein activation depending on GDP/GTP binding to establish a binary mode of action. This review summarizes the contributions of several Rab family members involved in trans-Golgi, early/late endosomes, and recycling endosomes during neurite development and axonal outgrowth. The regulation of some Rabs by guanine exchanging factors and GTPase activating proteins will also

Rab-mediated trafficking role in neurite formation

Neuronal cells are characterized by the presence of two confined domains, which are different in their cellular properties, biochemical functions and molecular identity. The generation of asymmetric domains in neurons should logically require specialized membrane trafficking to both promote neurite outgrowth and differential distribution of components. Members of the Rab family of small GTPases are key regulators of membrane trafficking involved in transport, tethering and docking of vesicles through their effectors. RabGTPases activity is coupled to the activity of guanine nucleotide exchange factors or GEFs, and GTPase-activating proteins known as GAPs. Since the overall spatiotemporal distribution of GEFs, GAPs and Rabs governs trafficking through the secretory and endocytic pathways, affecting exocytosis, endocytosis and endosome recycling, it is likely that RabGTPases could have a major role in neurite outgrowth, elongation and polarization. In this review we summarize the evidence linking the functions of several RabGTPases to axonal and dendritic development in primary neurons, as well as neurite formation in neuronal cell lines. We focused on the role of RabGTPases from the trans-Golgi network, early/late and recycling endosomes, as well as the function of some Rab effectors in neuritogenesis. Finally, we also discuss the participation of the ADP-ribosylation factor 6, a member of the ArfGTPase family, in neurite formation since it seems to have an important cross-talk with RabGTPases.Fil: Villarroel Campos, David. Universidad de Chile; ChileFil: Gastaldi, Laura Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Conde, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Caceres, Alfredo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: González Billault, Christian. Universidad de Chile; Chil

Rab35 functions in axon elongation are regulated by P53-related protein kinase in a mechanism that involves Rab35 protein degradation and the microtubule-associated protein 1B

© 2016 the authors. Rab35 is a key protein for cargo loading in the recycling endosome. In neuronal immortalized cells, Rab35 promotes neurite differentiation. Here we describe that Rab35 favors axon elongation in rat primary neurons in an activity-dependent manner. In addition, we show that the p53-related protein kinase (PRPK) negatively regulates axonal elongation by reducing Rab35 protein levels through the ubiquitin-proteasome degradation pathway. PRPK-induced Rab35 degradation is regulated by its interaction with microtubuleassociated protein 1B (MAP1B), a microtubule stabilizing binding protein essential for axon elongation. Consistently, axon defects found in MAP1B knock-out neurons were reversed by Rab35 overexpression or PRPK inactivation suggesting an epistatic relationship among these proteins. These results define a novel mechanism to support axonal elongation, by which MAP1B prevents PRPK-induced Rab35 degradation. Such a mechanism allows Rab35-mediated axonal elongatio

IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A

© 2018, The Author(s). Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A opera

Erratum to: IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A (Nature Cell Biology, (2018), 20, 8, (942-953), 10.1038/s41556-018-0141-0)

© 2018, The Publisher.In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article

Author Correction: IRE1α governs cytoskeleton remodeling and cell migration through a direct interaction with filamin A

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