The cytoplasmic dynein transport machinery and its many cargoes

Reck-Peterson, Samara L.; Redwine, William B.; Vale, Ronald D.; Carter, Andrew P.

doi:10.1038/s41580-018-0004-3

Cited by 523 publications

(736 citation statements)

References 244 publications

(242 reference statements)

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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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“…In support of a general role of neuronal β‐spectrins in promoting axonal transport via association with dynactin, pulldown experiments from mouse brain lysates show that βII‐spectrin is in a complex with p150 Glued (Lorenzo et al, ). Interestingly, recent cryo‐EM structures of dynactin indicate that p150 Glued is sterically less hindered than the Arp1 subunit (reviewed in Reck‐Peterson, Redwine, Vale, & Carter, , Urnavicius et al, ). Similarly, βV‐spectrin binds the dynactin subunit dynamitin (p50) in photoreceptor cells (Papal et al, ).…”

Section: Functional Roles Of the Spectrin And Ankyrin Assemblies In Nmentioning

confidence: 99%

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Lorenzo

2020

Cytoskeleton

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The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

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“…Microtubule plus‐end‐directed transport is mediated by kinesins and minus‐end directed transport largely by dynein. Whereas mammalian cells express only a single dynein motor domain, the human genome contains 45 kinesins, some 15 to 20 of which are thought to mediate neuronal vesicle transport . The large number of kinesin genes raises a fundamental question: Why are so many motors required to fulfill what appears to be the same basic function of moving vesicles towards the plus‐end of microtubules?…”

Section: Introductionmentioning

confidence: 99%

A novel strategy to visualize vesicle‐bound kinesins reveals the diversity of kinesin‐mediated transport

Yang

Bostick

Garbouchian

et al. 2019

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In mammals, 15 to 20 kinesins are thought to mediate vesicle transport. Little is known about the identity of vesicles moved by each kinesin or the functional significance of such diversity. To characterize the transport mediated by different kinesins, we developed a novel strategy to visualize vesicle‐bound kinesins in living cells. We applied this method to cultured neurons and systematically determined the localization and transport parameters of vesicles labeled by different members of the Kinesin‐1, ‐2, and ‐3 families. We observed vesicle labeling with nearly all kinesins. Only six kinesins bound vesicles that undergo long‐range transport in neurons. Of these, three had an axonal bias (KIF5B, KIF5C and KIF13B), two were unbiased (KIF1A and KIF1Bβ), and one transported only in dendrites (KIF13A). Overall, the trafficking of vesicle‐bound kinesins to axons or dendrites did not correspond to their motor domain preference, suggesting that on‐vesicle regulation is crucial for kinesin targeting. Surprisingly, several kinesins were associated with populations of somatodendritic vesicles that underwent little long‐range transport. This assay should be broadly applicable for investigating kinesin function in many cell types.

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The cytoplasmic dynein transport machinery and its many cargoes

Cited by 523 publications

References 244 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

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

A novel strategy to visualize vesicle‐bound kinesins reveals the diversity of kinesin‐mediated transport

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