Neurotubule

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Multicolor fluorescence image of a neuron. Neurotubules are stained in green and mitochondria are stained in red. Multicolor fluorescence image of a living PC-12 cell.jpeg
Multicolor fluorescence image of a neuron. Neurotubules are stained in green and mitochondria are stained in red.
Structure of a neurotubule. Microtubule id.svg
Structure of a neurotubule.

Neurotubules are microtubules found in neurons in nervous tissues. [1] Along with neurofilaments and microfilaments, they form the cytoskeleton of neurons. Neurotubules are undivided hollow cylinders that are made up of tubulin protein polymers [2] and arrays parallel to the plasma membrane in neurons. [3] Neurotubules have an outer diameter of about 23 nm and an inner diameter, also known as the central core, of about 12 nm. The wall of a neurotubule is about 5 nm in width. There is a non-opaque clear zone surrounding the neurotubule and it is about 40 nm in diameter. [3] Like microtubules, neurotubules are greatly dynamic and their length can be adjusted by polymerization and depolymerization of tubulin. [4]

Contents

Despite having similar mechanical properties, neurotubules are distinct from microtubules found in other cell types with regards to their function and intracellular arrangement. Most neurotubules are not anchored in the microtubule organizing center (MTOC) as conventional microtubules are. Instead, they are released for transport into dendrites and axons after their nucleation in the centrosome. Therefore, both ends of the neurotubules terminates in the cytoplasm instead. [5]

Neurotubules are crucial in various cellular processes in neurons. Together with neurofilaments, they help to maintain the shape of a neuron and provide mechanical support. Neurotubules also aid the transportation of organelles, vesicles containing neurotransmitters, messenger RNA and other intracellular molecules inside a neuron. [6]

Structure and dynamics

Formation of neurotubule Formation of Microtubule.png
Formation of neurotubule
An animation showing a 'catastrophe' event, which can rapidly reduce the length of a growing neurotubule.

Composition

Like microtubules, neurotubules are made up of protein polymers of α-tubulin and β-tubulin, globular proteins that are closely related. They join together to form a dimer, called tubulin. Neurotubules are generally assembled by 13 protofilaments which are polymerized from tubulin dimers. As a tubulin dimer consists of one α-tubulin and one β-tubulin, one end of the neurotubule is exposed with the α-tubulin and the other end with β-tubulin, these two ends contribute to the polarity of the neurotubule – the plus (+) end and the minus (-) end. The β-tubulin subunit is exposed on the plus (+) end. The two ends differ in their growth rate: plus (+) end is the fast-growing end while minus (-) end is the slow-growing end. Both ends have their own rate of polymerization and depolymerization of tubulin dimers, net polymerization causes the assembly of tubulin, hence the length of the neurotubules. [4]

Dynamic instability

The growth of neurotubules is regulated by dynamic instability. [7] It is characterized by distinct phases of growth and rapid shrinkage. The transition from growth to rapid shrinkage is called a 'catastrophe'. The reverse is called a 'rescue'.

Polarized neurotubule arrays

Neurons have a polarized neurotubule network. [8] Axons of most neurons contain neurotubules with plus (+) end uniformly pointing towards the axon terminal and minus (-) end orienting towards the cell body, similar to the general orientation of microtubules in other cell types. On the other hand, dendrites contain neurotubules with mixed polarities. Half of them point their plus (+) end towards the dendritic top and the other half points it towards the cell body, reminiscent of the anti-parallel microtubule array of the mitotic spindle.

The polarized neurotubule network forms the basis for selective cargo trafficking into axons and dendrites. [9] For example, when mutations occur in dynein, a motor protein that is crucial in maintaining the uniform orientation of axonal neurotubules, the neurotubule polarity in axon becomes mixed. [10] Dendritic proteins are mis-trafficked into axons as a result. [11]

For unpolarized neurons, the neurites contain 80% neurotubules with plus (+) end facing the terminal.[ citation needed ]

Axonal transport

Neurotubules are responsible for the trafficking of intracellular materials. The cargoes are transported by motor proteins that uses neurotubules as a 'track'. The axonal transport can be classified according to speed - fast or slow, and according to direction - anterograde or retrograde.

Fast and slow axonal transportation

The cargoes are transported at a fast rate or a slow rate. The fast axonal transport has a rate of 50–500 mm per day, while the slow axonal transport was found to be 0.4 mm per day in goldfish, 1–10 mm per day in mammalian nerve. Transport of insoluble protein contributes to the fast movement while the slow transport is transporting up to 40% - 50% soluble protein. [12] The speed of transport depends on the types of cargo to be transported. Neurotrophins, a family of proteins important for the survival of neuron, as well as organelles, such as mitochondria and endosomes, are transported at a fast rate. In contrast, structural proteins such as tubulin and neurofilament subunits are transported at lower rates. Proteins that are transported from the spinal cord to the foot can take up to a year to complete the journey. [13]

Anterograde transport and retrograde transport

A kinesin "walking" on a neurotubule to transport cargoes. Kinesin walking.gif
A kinesin "walking" on a neurotubule to transport cargoes.

Anterograde transport refers to the transportation of cargoes from the minus (-) end to the plus (+) end, whereas retrograde transport is the transportation of cargoes in the opposite direction. Anterograde transport is often the transportation from the cell body to the periphery of the neuron whereas retrograde transport brings organelles and vesicles away from the axon terminus to the cell body.

Anterograde transport is regulated by kinesins, a class of motor proteins. Kinesins have two head domains which work together like feet – one binds to the neurotubules, and then another binds while the former dissociates. The binding of ATP rises the affinity of kinesins for neurotubules. When ATP binds to one head domain, a conformational change will be induced in the head domain, causing it to bind tightly on the neurotubule. Another ATP then binds to another head domain while the former ATP is hydrolyzed and the head domain is dissociated. The process repeats itself as cycles so that kinesins move along the neurotubules together with the organelles and vesicular cargoes they carry. [14]

Retrograde transport is regulated by dyneins, also a class of motor proteins. It shares similar structures with kinesins, as well as the transporting mechanism. It transports cargoes from the periphery to the cell body in neurons.

Proteins associated with neurotubules

One most well-studied MAP is the Tau protein, due to its clinical significance in Alzheimer's disease. ProteineTau ita.jpg
One most well-studied MAP is the Tau protein, due to its clinical significance in Alzheimer's disease.

Microtubule-associated proteins (MAPs) are proteins that interact with microtubules by binding to their tubulin subunits and regulating their stability. The MAPs make-up of neurotubules is notably different from microtubules of non-neuronal cells. [15] For example, type II MAPs are exclusively found in neurons and not in other cells. The most well-studied ones include MAP2, and tau.

MAPs are differentially distributed within the neuronal cytoplasm. Their distribution varies across different stages of development of a neuron as well. A juvenile isoform of MAP2 is present on neurotubules of axons and dendrites of developing neurons but becomes down-regulated as neurons mature. The adult isoform of MAP2 is enriched in the neurotubules of dendrites and is virtually absent from axonal neurotubules. [16] In contrast, tau is absent on neurotubules of dendrites and its presence is limited to axonal neurotubules. The phosphorylation of tau at certain sites is required for tau to bind to neurotubules. In a healthy neuron, this process does not occur at a significant degree in dendrites, causing the absence of tau on dendritic neurotubules. The binding of tau of different isoforms and of different levels of phosphorylation regulate the stability of neurotubule. It is found that neurotubules of the neurons in embryonic central nervous system contain more highly phosphorylated tau than those in adults. [17] Additionally, tau is responsible for neurotubule bundling. [18]

Microtubule plus end tracking proteins (+TIPs) are MAPs that accumulates in the plus end of microtubules. In neurotubules, +TIPs control the neurotubule dynamics, direction of growth, and interaction with components of cell cortex. They are important in neurite extension and axon outgrowth. [19]

Many other non-neuron specific MAPs such as MAP1B and MAP6, are found on neurotubules. Moreover, the interaction between actin and some MAPs provide a potential link between neurotubules and actin filaments. [20]

Neurotubule disintegration in Alzheimer's disease. Alzheimers disease-microtubule disintegration.gif
Neurotubule disintegration in Alzheimer's disease.

Disruption in the integrity and dynamics of neurotubules can interfere with the cellular functions they perform and cause various neurological disorders.

Alzheimer's disease

In Alzheimer's disease, hyperphosphorylation of tau protein causes the dissociation of tau from neurotubules and tau misfolding. The aggregation of misfolded tau forms insoluble neurofibrillary tangles which is a characteristic finding in Alzheimer's disease. [21] This pathological change is called tauopathy. Neurotubules become prone to disintegration by microtubule-severing proteins when tau dissociates. [22] As a result, essential processes in the neuron such as axonal transport and neural communication will be disrupted, forming the basis for neurodegeneration. [23] Neurotubule disintegration is thought to occur by different mechanisms in axons and in dendrites.

The detachment of tau destabilizes the neurotubules by allowing excess severing by katanin, causing it to disintegrate. Neurotubules disintegration in the axon disrupts transport of mRNA and signalling molecules to the axon terminal. [22] For dendrites, new evidence suggests that an abnormal tau invasion into dendrites causes a heightened level of dendritic TTLL6 (Tubulin polyglutamylase TTLL6), which elevates the polyglutamylation status of the neurotubules in dendrites. [22] Because spastin displays strong preference for polyglutamylated microtubule, dendritic neurotubules become susceptible to spastin-induced disintegration. [22] The loss of neurotubule networks in dendrites and axons, along with the formation of neurofibrillary tangles results in the impairment in the trafficking of important cargoes across the cell, which can eventually lead to apoptosis. [24]

Lissencephaly

The characteristic "smooth brain" of an individual that suffers from lissencephaly, a defective neuronal migration disorder caused by mutations in neurotubule-related genes Lissencephaly.jpg
The characteristic "smooth brain" of an individual that suffers from lissencephaly, a defective neuronal migration disorder caused by mutations in neurotubule-related genes

Lissencephaly is a rare congenital condition in which the cerebrum loses its folds(gyri) and grooves(sulci), making the brain surface appear smooth. It is caused by defective neuronal migration. [25] The failure of post-mitotic neurons in reaching their proper positions leads to the formation of a disorganized and thickened four-layer neocortex instead of the normal six-layer neocortex. The severity of lissencephaly ranges from a complete loss of brain folds (agyria) to a general reduction in cortical folds(pachygyria).

Neurotubule is central to the migration mechanism of neurons. The defective neural migration in individuals affected by lissencephaly is caused by mutations associated with neurotubule-related genes, such as LIS1 and DCX . [26] LIS1 encodes an adaptor protein Lis1 that is responsible for stabilization of neurotubule during neuronal migration by minimizing neurotubule catastrophe. It also regulates the motor protein dynein that is crucial in the translocation of the nucleus along neurotubule. This action propels the soma of the neuron forward, which is an essential step in neuronal migration. [27] In addition, mutations in LIS1 is found to disrupt the uniform plus-end-distal polarity in axons in animal models, causing the mistrafficking of dendritic proteins into axons. [11] On the other hand, DCX encodes the protein doublecortin that interacts with Lis1 on top of supporting the 13 protofilament structure of neurotubule.

Chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy is a pathological change in neurons caused by the disruption in the dynamics of neurotubules by chemotherapy drugs, manifesting in pain, numbness, tingling sensation and muscle weakness in limbs. It is an irreversible condition that affects about one-third of chemotherapy patients. [28] Tubulin inhibitors inhibit mitosis in cancer cells by affecting the stability and dynamics of microtubules which forms the mitotic spindle responsible for chromosome segregation during mitosis, suppressing tumor growth.

However, the same drugs also affects neurotubules in neurons. Vinblastine binds to free tubulin and lower their polymerization capacity, promoting neurotubule depolymerization. On the other hand, paclitaxel binds to the cap of neurotubules, which prevents the conversion of tubulin-bound GTP into GDP, a process that promotes neurotubule depolymerization. For in vitro neurons treated with paclitaxel, the polarity pattern of neurotubule is disturbed, which can incur long term neuronal damage. In addition, over-stabilization of neurotubules interferes with their ability to perform essential cellular functions in neurons. [29]

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Dendrite</span> Small projection on a neuron that receives signals

A dendrite or dendron is a branched protoplasmic extension of a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. Electrical stimulation is transmitted onto dendrites by upstream neurons via synapses which are located at various points throughout the dendritic tree.

<span class="mw-page-title-main">Microtubule</span> Polymer of tubulin that forms part of the cytoskeleton

Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 and 15 nm. They are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin into protofilaments that can then associate laterally to form a hollow tube, the microtubule. The most common form of a microtubule consists of 13 protofilaments in the tubular arrangement.

<span class="mw-page-title-main">Neuron</span> Electrically excitable cell found in the nervous system of animals

A neuron, neurone, or nerve cell is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.

<span class="mw-page-title-main">Dynein</span> Class of enzymes

Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements important in mitosis, and drives the beat of eukaryotic cilia and flagella. All of these functions rely on dynein's ability to move towards the minus-end of the microtubules, known as retrograde transport; thus, they are called "minus-end directed motors". In contrast, most kinesin motor proteins move toward the microtubules' plus-end, in what is called anterograde transport.

Axoplasm is the cytoplasm within the axon of a neuron. For some neuronal types this can be more than 99% of the total cytoplasm.

Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and microfilaments (7 nm), they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into six types based on their gene organization and protein structure. Types I and II are the keratins which are expressed in epithelia. Type III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Type IV consists of the neurofilament proteins NF-L, NF-M, NF-H and α-internexin. Type V consists of the nuclear lamins, and type VI consists of the protein nestin. The type IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive type IV gene.

<span class="mw-page-title-main">Soma (biology)</span> Portion of a brain cell containing its nucleus

In cellular neuroscience, the soma, perikaryon, neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. Although it is often used to refer to neurons, it can also refer to other cell types as well, including astrocytes, oligodendrocytes, and microglia. There are many different specialized types of neurons, and their sizes vary from as small as about 5 micrometres to over 10 millimetres for some of the smallest and largest neurons of invertebrates, respectively.

In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to the stability of the cell and its internal structures and the transport of components within the cell.

<span class="mw-page-title-main">Axonal transport</span> Movement of organelles

Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplasm of its axon called the axoplasm. Since some axons are on the order of meters long, neurons cannot rely on diffusion to carry products of the nucleus and organelles to the ends of their axons. Axonal transport is also responsible for moving molecules destined for degradation from the axon back to the cell body, where they are broken down by lysosomes.

A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before differentiation is complete.

<span class="mw-page-title-main">Protein filament</span> Long chain of protein monomers

In biology, a protein filament is a long chain of protein monomers, such as those found in hair, muscle, or in flagella. Protein filaments form together to make the cytoskeleton of the cell. They are often bundled together to provide support, strength, and rigidity to the cell. When the filaments are packed up together, they are able to form three different cellular parts. The three major classes of protein filaments that make up the cytoskeleton include: actin filaments, microtubules and intermediate filaments.

<span class="mw-page-title-main">Microtubule-associated protein 2</span> Mammalian protein found in Homo sapiens

Microtubule-associated protein 2 is a protein in humans that is encoded by the MAP2 gene.

<span class="mw-page-title-main">KIF23</span> Protein-coding gene in the species Homo sapiens

Kinesin-like protein KIF23 is a protein that in humans is encoded by the KIF23 gene.

Collapsin response mediator protein family or CRMP family consists of five intracellular phosphoproteins of similar molecular size and high (50–70%) amino acid sequence identity. CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules. Cleaved forms of CRMPs have also been linked to neuron degeneration after trauma induced injury.

<span class="mw-page-title-main">KIF1A</span> Motor protein in humans

Kinesin-like protein KIF1A, also known as axonal transporter of synaptic vesicles or microtubule-based motor KIF1A, is a protein that in humans is encoded by the KIF1A gene.

<span class="mw-page-title-main">Kinesin-like protein KIF11</span> Protein-coding gene in the species Homo sapiens

Kinesin-like protein KIF11 is a molecular motor protein that is essential in mitosis. In humans it is coded for by the gene KIF11. Kinesin-like protein KIF11 is a member of the kinesin superfamily, which are nanomotors that move along microtubule tracks in the cell. Named from studies in the early days of discovery, it is also known as Kinesin-5, or as BimC, Eg5 or N-2, based on the founding members of this kinesin family.

<span class="mw-page-title-main">KIF15</span> Protein-coding gene in the species Homo sapiens

Kinesin family member 15 is a protein that in humans is encoded by the KIF15 gene.

<span class="mw-page-title-main">CAMSAP2</span> Protein found in humans

Calmodulin-regulated spectrin-associated protein family member 2 (CAMSAP2) is a protein in humans that is encoded by the CAMSAP2 gene. CAMSAP2 possesses a microtubule-binding domain near the C-terminal region where "microtubule interactions" occur. On the C-terminal regions, protein to protein interactions are accelerated by three coiled-coil domains, which function as molecular spacers. CAMSAP2 acts as a microtubule minus-end anchor and binds microtubules through its CKK domain. CAMSAP2 is necessary for the proper organization and stabilization of interphase microtubules. The protein also plays a role in cell migration. CAMSAP2 stabilizes and attaches microtubule minus ends to the Golgi through the AKAP9 complex and myomegalin. CLASP1 proteins are responsible for microtubule stability which are not required for the Golgi tethering. When no centromeres are present, AKAP9 and CAMSAP-2 dependent pathways of the microtubule minus ends become a dominant force and must exist in order to observe the maintenance of microtubule density.

Casper Hoogenraad is a Dutch Cell Biologist who specializes in molecular neuroscience. The focus of his research is the basic molecular and cellular mechanisms that regulate the development and function of the brain. As of January 2020, he serves as Vice President of Neuroscience at Genentech Research and Early Development.

References

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