A CRMP4‐dependent retrograde axon‐to‐soma death signal in amyotrophic lateral sclerosis

Maimon, Roy; Ankol, Lior; Pery, Tal Gradus; Altman, Topaz; Ionescu, Ariel; Weissova, Romana; Ostrovsky, Michael; Tank, Elizabeth M.H.; Alexandra, Gayster; Shelestovich, Natalia; Opatowsky, Yarden; Dori, Amir; Barmada, Sami J.; Balastik, Martin; Perlson, Eran

doi:10.15252/embj.2020107586

Cited by 12 publications

(13 citation statements)

References 81 publications

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“…Our analysis on A. nidulans diploids has shown that the kinA K895 * or the kinA (1-894) -GFP allele is also a gain-of-function mutation that partially affects dynein-mediated early endosome transport in the presence of a wild-type copy of kinA (Supplemental Figure 2). As dynein defects have been linked to ALS (Chevalier-Larsen and Holzbaur, 2006; Gershoni-Emek et al, 2016; Hafezparast et al, 2003; Ikenaka et al, 2013; Kieran et al, 2005; LaMonte et al, 2002; Maimon et al, 2021; Mentis et al, 2022; Münch et al, 2004; Stavoe and Holzbaur, 2019; Ström et al, 2008), it is likely that a partial defect in dynein function contributes to ALS caused by the gain-of-function mutations in KIF5A. Future studies will be needed to test this idea.…”

Section: Resultsmentioning

confidence: 99%

“…Cytoplasmic dynein is the minus-end-directed microtubule motor, and defects in dynein and/or its regulator dynactin have been implicated in ALS (Chevalier-Larsen and Holzbaur, 2006; LaMonte et al, 2002; Maimon et al, 2021; Münch et al, 2004). Some vesicular cargos bind both dynein and kinesin-1 via the same cargo adapter (Cox and Spradling, 2006; Fenton et al, 2021; Fu and Holzbaur, 2014)(Canty et al, 2021, bioRxiv; Celestino et al, 2021, bioRxiv), and in this case, loss of kinesin-1 autoinhibition may help overcome the force of dynein to change cargo distribution (Baron et al, 2022; Kelliher et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Qiu

Zhang

Xiang

2022

Preprint

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Kinesin-1 undergoes autoinhibition but its functional significance has been unclear. Kinesin-1 transports multiple cargoes including cytoplasmic dynein to the microtubule plus ends. From a genetic screen for Aspergills mutants defective in dynein-mediated early endosome transport, we identified a kinesin-1 mutation kinAK895* that disrupts kinesin-1 autoinhibition. Consistent with kinAK895* making kinesin-1 constitutively active, the mutant proteins accumulate abnormally near the microtubule plus ends. Unexpectedly, our genetic data show that kinesin-1 autoinhibition is unnecessary for transporting its cargoes such as secretory vesicles. Dynein accumulates normally at the microtubule plus ends in the kinAK895* mutant. However, the frequency but not the speed of dynein-mediated early endosome transport is significantly decreased, indicating that kinesin-1 autoinhibition facilitates dynein to initiate its cargo transport. Furthermore, kinesin-1 autoinhibition promotes dynein cargo initiation in a way mechanistically distinct from LIS1-promoted dynein switching from its autoinhibited form. Thus, while dynein activation involves dynactin, cargo adapter and LIS1, this study adds kinesin-1 autoinhibition as a new regulatory factor in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Qiu

Zhang

Xiang

2022

Preprint

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“…Additionally, Sema3A-CRMPs signaling has been suggested to be involved in ALS pathogenesis because Sema3A is upregulated in the motor cortex of ALS patients and the terminal Schwann cell adjacent to neuromuscular junctions (NMJs) in SOD1 G93A mice ( De Winter et al, 2006 ; Körner et al, 2016 ). Moreover, elevation of both Crmp4 and Crmp4-dynein complex leads to neuronal death in ALS model mice ( Duplan et al, 2010 ; Maimon et al, 2021 ) while the inhibition of Crmp2 phosphorylation ameliorates the motor phenotype of SOD1 G93A mice ( Numata-Uematsu et al, 2019 ). However, it remains uncertain whether CRMP1 is involved in the pathomechanism of ALS.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice

Asano

Nakamura

Kawamoto

et al. 2022

eNeuro

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1 G93A ). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1 G93A mice using Crmp1 S522A (Ser522→Ala) knock-in ( Crmp1 k i /ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out ( Crmp1 −/− ) mice, respectively. Crmp1 ki / ki / SOD1 G93A mice showed longer latency to fall in a rotarod test while Crmp1 −/− / SOD1 G93A mice showed shorter latency compared with SOD1 G93A mice. Survival was prolonged in Crmp1 ki / ki / SOD1 G93A mice but not in Crmp1 −/− / SOD1 G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in Crmp1 ki / ki / SOD1 G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1 ki / ki / SOD1 G93A and Crmp1 −/− / SOD1 G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.

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“…ALS, CMTs and others). We and others have over the years developed several stem cell in vitro platforms for MNs combining stem cells, bioengineering, and imaging 10,15–18 to faithfully recapitulate their biology and mechanisms of disease in ALS. However, these in vitro models fail to recapitulate the length of motor axons, which is in most cases the used culture systems generate cells with axons ranging from 1-200um 19 to at most 1 millimeter 20,21 or do not provide a controlled environment for measuring axonal length, lacking the modelling of potential biophysical constraints which long axons provide in vivo .…”

Section: Introductionmentioning

confidence: 99%

“…ALS, CMTs and others). We and others have over the years developed several stem cell in vitro platforms for MNs combining stem cells, bioengineering, and imaging 10,[15][16][17][18] to faithfully recapitulate their biology and mechanisms of disease in ALS.…”

Section: Introductionmentioning

confidence: 99%

“Axonal Length Determines distinct homeostatic phenotypes in human iPSC derived motor neurons on a bioengineered platform”

Hagemann

González

Guetta

et al. 2021

Preprint

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Stem cell-based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant for neurons covering long range connections such as spinal motor neurons (MNs). The axons of these neurons extend up to 1m in length and require a complex interplay of mechanisms to maintain cellular homeostasis. It follows that shorter axons in conventional cultures may not faithfully capture important aspects of their longer counterparts. Here we directly address this issue by establishing a bioengineered platform to assemble arrays of human axons ranging from micrometers to centimeters, permitting systematic investigation of the effects of length on human axonal biology for the first time. With this approach, we reveal a link between length and metabolism in human MNs in vitro, where axons above a threshold size induce specific molecular adaptations in cytoskeleton composition, functional properties, local translation and mitochondrial homeostasis. Our findings specifically indicate the existence of a length-dependent mechanism that switches homeostatic processes within human MNs in order to sustain long axons. Our findings have critical implications for in vitro modelling of several neurodegenerative disorders and reinforce the importance of modelling cell shape and biophysical constraints with fidelity and precision in vitro.

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A CRMP4‐dependent retrograde axon‐to‐soma death signal in amyotrophic lateral sclerosis

Cited by 12 publications

References 81 publications

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice

“Axonal Length Determines distinct homeostatic phenotypes in human iPSC derived motor neurons on a bioengineered platform”

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