Motor–cargo adaptors at the organelle–cytoskeleton interface

Cross, Jessica A.; Dodding, Mark P.

doi:10.1016/j.ceb.2019.02.010

Cited by 66 publications

(78 citation statements)

References 66 publications

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“…We found that transport of both mitochondria and RNA granules in sMNs is perturbed by arginine-rich DPRs. Given the widespread roles of kinesin-1 and dynein in intracellular transport (83,84), as well as our discovery of other classes of microtubule motors in the PR30 interactome from sMNs, it is likely that the trafficking of several cargoes is disrupted by these peptides. Whether altered translocation of a specific cargo type is of particular significance for C9-ALS/FTD remains to be resolved.…”

Section: Discussionmentioning

confidence: 99%

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Fumagalli

Young

Boeynaems

et al. 2019

Preprint

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Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies. INTRODUCTIONA GGGGCC (G4C2) repeat expansion in the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD) (1,2). Since the association between the hexanucleotide repeat expansions (HREs) and these neurodegenerative diseases was discovered, three non-mutually exclusive pathological mechanisms have been proposed. The first is a loss-of-function scenario due to decreased expression of C9orf72 transcript and protein observed in C9-ALS/FTD patients (1,3). The second is an RNA gain-of-function mechanism caused by the accumulation of expanded repeat transcripts that sequester numerous RNA-binding proteins (4-9). The third proposed mechanism is a protein gain-of-function via the generation of pathological dipeptide repeat proteins (DPRs) originating from non-ATG mediated translation of the expanded repeat transcripts (10-13).This repeat-associated non-ATG (RAN) translation occurs in all reading frames of sense and antisense transcripts resulting in five DPR proteins: poly-GR and poly-GA exclusively from the sense transcript, poly-PR and poly-PA exclusively from the antisense transcript, and poly-GP from both transcripts (10-13). DPRs are found in cytoplasmic inclusions in C9-ALS/FTD post-mortem brain and spinal cord tissue, and also have been detected in motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) (5,10,11,(14)(15)(16)(17)(18). The arginine-rich DPRs -poly-PR and poly-GR -are potently toxic in numerous disease models (14,(19)(20)(21)(22)(23)(24)(25)(26)(27), and have been shown to cause mitochondrial (28,29) and endoplasmic reticulum stress (26), as well as disturbances...

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Section: Discussionmentioning

confidence: 99%

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Fumagalli

Young

Boeynaems

et al. 2019

Preprint

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“…Neuronal circuit connectivity relies on precise spatial and temporal delivery of specific organelles and vesicles to different neuronal subcellular compartments (Tojima et al, 2007, 2011; Akiyama et al, 2016). In this context, different regulatory and adaptor proteins are emerging as critical to assist opposite teams of molecular motors in their fine-tuned delivery of specific cargoes in developing neurons (Akhmanova and Hammer, 2010; Fu and Holzbaur, 2014; Schlager et al, 2014; Cross and Dodding, 2019; Olenick and Holzbaur, 2019). Although in vitro studies have highlighted the importance of the regulation of cargo transport velocity for axon outgrowth (Schlager et al, 2010, 2014), an in vivo role for such mechanisms in axon navigation processes is still lacking.…”

Section: Discussionmentioning

confidence: 99%

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

Atkins

Gasmi

Bercier

et al. 2019

Journal of Cell Biology

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Neuronal connectivity relies on molecular motor-based axonal transport of diverse cargoes. Yet the precise players and regulatory mechanisms orchestrating such trafficking events remain largely unknown. We here report the ATPase Fignl1 as a novel regulator of bidirectional transport during axon navigation. Using a yeast two-hybrid screen and coimmunoprecipitation assays, we showed that Fignl1 binds the kinesin Kif1bβ and the dynein/dynactin adaptor Bicaudal D-1 (Bicd1) in a molecular complex including the dynactin subunit dynactin 1. Fignl1 colocalized with Kif1bβ and showed bidirectional mobility in zebrafish axons. Notably, Kif1bβ and Fignl1 loss of function similarly altered zebrafish motor axon pathfinding and increased dynein-based transport velocity of Rab3 vesicles in these navigating axons, pinpointing Fignl1/Kif1bβ as a dynein speed limiter complex. Accordingly, disrupting dynein/dynactin activity or Bicd1/Fignl1 interaction induced motor axon pathfinding defects characteristic of Fignl1 gain or loss of function, respectively. Finally, pharmacological inhibition of dynein activity partially rescued the axon pathfinding defects of Fignl1-depleted larvae. Together, our results identify Fignl1 as a key dynein regulator required for motor circuit wiring.

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“…Kinesore treatment results in dynamic looping and bundling of microtubules within the cytoplasm and their extrusion from the cell body as membrane-bound projections. This renders microtubules from within the cell accessible for cryo-EM studies (Cross and Dodding, 2019;Randall et al, 2017). Here we describe the discovery of filamentous actin (F-actin) inside the microtubule lumen through in situ cryo-electron tomography (cryo-ET) analysis of these small molecule-induced projections.…”

Section: Introductionmentioning

confidence: 99%

In situ cryo-electron tomography reveals filamentous actin within the microtubule lumen

Paul

Mantell

Borucu

et al. 2020

Journal of Cell Biology

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Microtubules and filamentous (F-) actin engage in complex interactions to drive many cellular processes from subcellular organization to cell division and migration. This is thought to be largely controlled by proteins that interface between the two structurally distinct cytoskeletal components. Here, we use cryo-electron tomography to demonstrate that the microtubule lumen can be occupied by extended segments of F-actin in small molecule–induced, microtubule-based, cellular projections. We uncover an unexpected versatility in cytoskeletal form that may prompt a significant development of our current models of cellular architecture and offer a new experimental approach for the in situ study of microtubule structure and contents.

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Motor–cargo adaptors at the organelle–cytoskeleton interface

Cited by 66 publications

References 66 publications

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

In situ cryo-electron tomography reveals filamentous actin within the microtubule lumen

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