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Selective motor activation in organelle transport along axons

Abstract

The active transport of organelles and other cargos along the axon is required to maintain neuronal health and function, but we are just beginning to understand the complex regulatory mechanisms involved. The molecular motors, cytoplasmic dynein and kinesins, transport cargos along microtubules; this transport is tightly regulated by adaptors and effectors. Here we review our current understanding of motor regulation in axonal transport. We discuss the mechanisms by which regulatory proteins induce or repress the activity of dynein or kinesin motors, and explore how this regulation plays out during organelle trafficking in the axon, where motor activity is both cargo specific and dependent on subaxonal location. We survey several well-characterized examples of membranous organelles subject to axonal transport — including autophagosomes, endolysosomes, signalling endosomes, mitochondria and synaptic vesicle precursors — and highlight the specific mechanisms that regulate motor activity to provide localized trafficking within the neuron. Defects in axonal transport have been implicated in conditions ranging from developmental defects in the brain to neurodegenerative disease. Better understanding of the underlying mechanisms will be essential to develop more-effective treatment options.

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Fig. 1: Microtubule and motor organization in neurons.
Fig. 2: Motor autoinhibition and activation.
Fig. 3: Models of intermotor coordination.
Fig. 4: Many motor effectors induce both anterograde and retrograde transport.
Fig. 5: Axonal transport of mitochondria, endolysosomes, and synaptic components.
Fig. 6: Axonal transport of autophagic vacuoles and signalling endosomes.

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Acknowledgements

This work was supported by NIH grants R35 GM126950 and RM1 GM136511 to E.L.F.H. and an NSF Graduate Research Fellowship (DGE-1845298) to S.E.C. The authors declare no competing financial interests. They thank J. Aiken and A. Fenton for insights and discussions.

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Correspondence to Erika L. F. Holzbaur.

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Glossary

Signalling endosomes

Membranous organelles formed by internalizing a neurotrophin-bound receptor, which is then trafficked to the soma to trigger downstream effects, including transcriptional changes. Following signalling, the receptor may be degraded or recycled back to the plasma membrane.

Coiled-coil

(CC). Structural motif in which multiple α-helices are coiled together to form a supercoil. The primary sequence is made up of a series of heptad repeats including both hydrophobic and charged residues. CC domains are often stiff rods that function as molecular spacers.

Dynein-activating adaptors

Dynein effectors that activate dynein motility and link dynein — directly or indirectly — to cargo. Most dynein-activating adaptors contain an extended coiled-coil motif (~38 nm) flanked by conserved motifs for dynein and dynactin binding.

Tetratricopeptide repeats

(TPRs). Common structural motifs consisting of 3–16 tandem repeats that form α-helices, which typically fold together to form a leaner solenoid domain. The TPR motif in kinesin light chain is commonly the binding site for kinesin 1-activating proteins.

Leucine–phenylalanine–proline (LFP) motif

A short unstructured motif (also referred to as an ‘LFP–acidic motif’) involved in protein–protein interactions. The LFP motif in kinesin light chain is commonly the binding site for kinesin 1-activating proteins.

Hereditary spastic paraplegia

A group of rare inherited peripheral nerve disorders characterized by weakness and stiffness of the leg muscles which progress over time.

Amyotrophic lateral sclerosis

Also known as Lou Gehrig disease, a progressive nervous system disease resulting in muscle weakness and other motor symptoms. The causes differ, and onset is typically between 40 years of age and 65 years of age.

Phox homology (PX) or pleckstrin homology (PH) domains

Lipid-binding domains that interact with phosphoinositides, facilitating membrane localization.

ARP1 filament

Dynactin sub-complex consisting of a filament made up of actin-related protein 1 (ARP1), a pointed-end complex (ARP11, p62, p25 and p27) and a barbed-end complex (CapZα and CapZβ).

p150Glued

Dynactin subunit protein containing a microtubule-binding CAP-Gly domain and a globular shoulder domain connected by a flexible coiled-coil-enriched linker domain.

CC1 box motif

Common dynein-activating adaptor motif that forms a hydrophobic pocket in which the dynein light intermediate chain helix 1 inserts itself.

Spindly motif

Common dynein-activating adaptor motif that mediates interaction with the pointed-end complex of the ARP1 filament of dynactin.

Glued motif

Common dynein-activating adaptor motif that mediates interaction with the second coiled-coil domain of the p150Glued subunit of dynactin.

O-GlcNAcylation

A reversible post-translational modification whereby a monosaccharide (O-linked β-N-acetylglucosamine (O-GlcNAc)) is attached to a serine or threonine residue. O-GlcNAcylation typically occurs in response to changes in nutrient state or stress.

Active zone

The region of the presynapse where synaptic vesicle fusion and neurotransmitter release occur.

En passant synapses

Presynapses located along the axon shaft.

Axon initial segment

The short region (20–60 µm) of the axon immediately adjacent to the soma which acts as a selective filter to limit axonal transport and initiates action potentials (electrical signalling).

Calmodulin

A secondary messenger protein activated by the binding of Ca2+ involved in numerous cell signalling pathways.

JNK

(JUN amino-terminal kinase). A family of mitogen-activated protein kinases that respond to stress stimuli and trigger signalling cascades implicated in inflammation, gene expression, DNA repair, neuronal plasticity, and cell death or senescence.

Piccolo–Bassoon transport vesicles

trans-Golgi-derived vesicles that transport Piccolo and Bassoon, two large scaffolding proteins that help form the active zone, from the soma to the presynapses.

Amyloid precursor protein

(APP). A transmembrane protein enriched at synapses believed to be important for synaptic formation and plasticity. APP can be differentially cleaved, and the cleavage product, β-amyloid, accumulates in neurodegenerative diseases, including Alzheimer disease.

Huntingtin

(HTT). A large scaffolding protein (~350 kDa) involved in multiple pathways, including axonal transport and transcription. Expansion of the polyglutamine repeat region in the amino terminus of the protein results in Huntington disease.

AKT

Also known as protein kinase B, a family of serine/threonine kinases involved in cell survival, proliferation and metabolism.

ATG8

A family of ubiquitin-like proteins localized primarily to the autophagosomal membrane and necessary for both selective and bulk autophagy, autophagosome biogenesis and autophagosome–lysosome fusion. LC3B is a well-characterized member of this family commonly used as a marker for autophagosomes in mammalian cells.

Neurotrophin

Extracellular-signalling factor (typically a small protein or peptide) that triggers cascades in neurons, including to survival, development/growth and function.

Spinal muscular atrophy with lower-extremity predominance

An inherited neuromuscular disorder characterized by muscle weakness and wasting in the lower limbs, which primarily appears in childhood.

Lissencephaly

A neurodevelopmental disorder characterized by a ‘smooth brain’ without normal cortical folds.

Microcephaly

A birth defect wherein a baby’s head is smaller than normal owing to abnormal brain development.

Huntington disease

A neurodegenerative disease resulting from a polyglutamine expansion in the gene encoding huntingtin (HTT). Symptoms typically appear in early adulthood, include both motor and cognitive problems, and worsen over time.

Parkinson disease

A progressive neurodegenerative disease resulting from the degradation of the dopaminergic neurons in the substantia nigra, part of the midbrain. Symptoms include tremors, stiffness and difficulty moving, especially controlling or initiating movement.

Lysosomal storage disorder

A class of inherited metabolic disorders wherein lysosomal degradation is defective. They can affect a range of tissues, including the brain, eyes, muscles and kidneys. Most patients develop symptoms during childhood, and these worsen over time.

ESCRT

Endosomal sorting complexes required for transport (0–III) made up of cytosolic proteins that facilitate membrane remodelling including, multivesicular body formation and membrane abscission during cytokinesis. They can also be involved in protein–protein interactions, especially to recruit other proteins to the endosomal membrane.

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Cason, S.E., Holzbaur, E.L.F. Selective motor activation in organelle transport along axons. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00491-w

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