2014 Group 4 Project

From CellBiology

UNSW ANAT3231 Course Coordinator Dr Mark Hill
2014 Projects: Group 1 | Group 2 | Group 3 | Group 4

Neuron Soma to Processes


Detailed diagram of neurone and its components

Neurones/Neurons/Nerve cells are cells that process and transmit chemical and electrical signals. They connect to each other forming things called neural networks. They are an integral part of the nervous system and different types help us function through everyday life. There are sensory neurones that tell the rest of the brain about the external (sight, sound, touch) and internal environment. Motor neurones that directly or indirectly control muscles and other output neurons stimulate glands and organs. Lastly interneurons that help neurones connect to one another and relay information.

A typical neurone is composed of three main parts. A cell body also known as the soma, an axon and dendrites.

The soma of a neurone contains the cell nucleus amongst a variety of other organelles. Material that needs to be moved from the soma to their processes go via the axon hillock. The axon hillock connects the soma to the axon.

The axon of a neurone is a relatively long projection with a constant radius. Materials that pass through the axon hillock then have various motor proteins that move the material along the microtubules of the axon. The process of movement along the axon is termed axoplasmic transport and is discussed in detail below. The axon then synapse on processes such as other neurone, muscles and glands cells. As well as moving different material the axon is capable of conducting electrical impulses away from the cell body.

Dendrites are the 'tree' of the soma. They branch out to provide a large surface area for other dendrites and axons to synapse on and transmit information to. Dendrites taper off in shape and are relatively short compared to axons. Dendrites conduct electrical stimulations and pass this onto the cell body. They are very important in determining the extent of action potential produced by the neurone.

Both dendritic and and axoplasmic transport are essential for basic functioning. Without optimum performance and conditions there can be a host of issues. These can range from physical defects to neurological defects.

Axoplasmic and Dendridic Transport

Adaptor proteins, or scaffolding proteins are an essential components axoplasmic and dendritic transport. The proteins are recognised by molecular motors and promote either axoplasmic or dendritic transport. The table below briefly summarises the structures, mechanisms, cargo, motors and polarity of structures involved in both axoplasmic and dendritic transport.

Summary of Axoplasmic and Dendritic Transport[1]
Axoplasmic Transport Dendritic Transport
Structures Neuron soma, axon in particular axon skeleton
  • Neurofilaments
  • Intermediate filaments
  • Microtubules
Neuron soma, dendrites in particular dendritic braches and spine
  • Neurofilaments
  • Intermediate filaments
  • Microtubules
Mechanisms (It is essential to note that these mechanism are not mutually exclusive) Axoplasmic preferences: specific axonal motors. Polarised recognition stems from motor domains

Specific degradation of the motor proteins in axon localizations

Dendritic preferences: are defined by specific dendritic motors. Polarised recognition stems from motor domains

Specific degradation of the motor proteins in dendritic localizations

Cargos Membranous (Golgi derived vesicles and Endocytic vesicles)

Non Membranous (Cytoskeletal polymers)

Membranous (Golgi derived vesicles and Endocytic vesicles)

Non Membranous (Cytoskeletal polymers)

Motors Kinesin, Dyein, Dynactin Kinesin specifically KIF17
Polarity Microtubule plus ends are toward the axonal terminal Microtubule polarity in proximal dendrites is mixed

Distal dendrites plus ends directed towards tips

Axonal Transport

Axonal transport is a specialized and well-developed mechanism of transporting intracellular materials along the axon. It involves active movement of cargo bound to specific motor proteins that travel along microfilament tracks within the axoplasm to target destinations [2]. It is a bidirectional process - movement of materials towards the neuron cell body is called retrograde transport, and movement away from the neuron cell body is called anterograde transport. It is important to note that direction of movement is not restritcted to one axon - bidirectional movement can occur within the same axon, but along different sides of microtubule tracks. The only exception to this is mitochondria, which is distinct in its ability to move in both directions during transit. Furthermore, the type of structure carried by the cargo determines the overall rate of transport along the axon: membranous bound structures travel at slow rates, or via slow transport, whilst non-membranous structures travel at fast rates, or via fast mechanisms [3].

<mediaplayer>https://www.youtube.com/watch?v=2-L-Ts6fsks</mediaplayer> This simple video provides a great visual introduction to axonal transport without delving into the specifics of mechanisms, cargo and types of rate components. Cargo can clearly be seen traveling along the axon in both directions


There are several, primary structures worth identifying in relation to the underlying mechanisms axonal transport: the axon, its cytoskeleton, the neuron cell body (or soma), and specialized motor proteins.


Though microscopic in diameter (generally one micrometer, in humans), these slender, cylindrical processes of neurons can extend to dramatic distances several thousand times greater than the size of the neuron’s cell body - projecting up to more than one metre in length in humans (http://www.sciencedaily.com/articles/a/axon.htm) Axonal transport is characterised by its impressive ability to move cargo along these great lengths.

Axonal Cytoskeleton

The cytoskeletons that comprise the overall structure of the axon provide neuron support, but are also highly dynamic - continuously changing in shape and size to accommodate for essential functions of neurons [4]. They are comprised of:

  • Neurofilaments: Composed of actin that form evenly spaced rings around the circumference to provide protoplasmic stability and strength. [5]
  • Intermediate filaments (or microfilaments): have branching capabilities to provide flexibility and structural stability during dynamic changes [5]
  • Microtubules: long, hollow cylinders that contract and grow in relation to axon outgrowth and regeneration. They are comprised of polymerized α- and β-tubulin dimers, functionally causing a polarity. Protofilaments will expose one end, “plus end”, whilst other end will have exposed B subunits, as the “minus end” [6]. Additionally, the structure of microtubules act as “railway lines” or “tracks” to provide a pathway during axonal transport [6].

Together, each component of the axonal cytoskeleton have specific individual, yet coordinating roles in the maintenance of strength, flexibility and renewal of the overall axonal structure. It is therefore of high importance for the axon’s growth and survival that newly synthesized proteins from the soma are actively transported at an efficient rate.


Due to the dynamic nature of the cytoskeleton, the proteins that comprise the complex structure must be actively renewed to maintain optimum function. However, there is a lack of local ribosomes in the axoplasm, so synthesis of proteins is primarily restricted within the confines of the soma [7].The soma, approximately 10-25 micrometres in diameter, contains Nissl substance, granules of rough endoplasmic reticulum (RER) and free ribosomes responsible for synthesis of cytoskeletal components that comprise the axonal structure[8] [9]. The rate of protein synthesis must be in sync with the changing nature of the axon in order to maintain its overall structure, and thus, proper functioning.

Golgi Apparatus

The golgi apparatus is an organelle found within the soma of the neuron. It contains approximately 40-100 stacks of membrane bound structures called cisternae[10]. In relation to axonal transport, the golgi apparatus is important for the following reasons:

1. receives and processes membranous proteins from the RER in the soma. It modifies, sorts and packages the membranous proteins into appropriate cargo before it is bound to motor proteins for transport [11]

2. Processing of secretory proteins for fast anterograde axonal transport.[11]

3. Secretion of lysosomes, which are responsible for the degradation of molecules that are brought back to the soma from the distal axon via fast retrograde axonal transport[12]

Motor Proteins

Motor proteins are significantly responsible for the mechanisms of transporting materials in axonal transport. They carry grouped individual materials as cargo to specific destinations along microtubule tracks. The three primary motor proteins in the process of axonal transport are kinesin, dynein and dynactin. Due to the important yet complex structure and functional mechanisms of motor proteins, they will be described in more detail in the Motor Proteins section


There is much needed research to be conducted in relation to the mechanisms of axonal transport, but there have been recent studies providing essential ground knowledge for the basis of understanding [2]. The process of axonal transport occurs in neurons, more specifically, within the axoplasm. It is highly characterised by its ability to transport essential materials along the great lengths of the axon [13]. The soma of the neuron has significant roles in regards to neuronal metabolism, functioning as the primary site of protein synthesis. Also, newly synthesized intracellular materials and organelles destined for transport originate here.

After synthesis, each type of material is distinctly packaged and sorted into appropriate cargo, depending on their molecular composition. [14]. Cargo destined for retrograde movement, (i.e. towards the minus ends of tubules) are specifically bound to motor protein dynein. Cargo destined for anterograde movement (i.e. away from the some, towards the plus ends of microtubules) are specifically bound to kinesin[15]. Motor proteins recognize the arrangement of the microtubule track polarity and functionally react to carry cargo in a unidirectional manner. Kinesin carries cargo in an anterograde direction (towards the plus ends, away from the soma), whilst dynein carries cargo in a retrograde direction (towards the minus ends, away from the soma) [16]. Movement is active, often powered by the hydrolysis of ATP. Additionally, shrinkage and growth of the axon may generate force that influences motor protein movement along the microtubule track.

Movement of motor proteins along microtubule tracts can distinctly vary in speeds. Therefore, mechanisms of axonal transport can be divided into fast and slow axonal transport, depending upon the overall net rate of transit[17]

Note: Underlying mechanisms at the level of motor proteins are described in detail here

Types of Transport

The type of structure within cargo carried by the motor proteins determines the rate of transport along the axon [18] Membranous structures tend to transit along the axon at fast speeds, and therefore travel via fast axonal transport. On the other hand, non-membranous structures travel along the axon at slower speeds, thus classified as slow axonal transport[19] .

Brief Overview: Major Rate Components

DIRECTION Anterograde Retrograde Mitochondrial SCa SCb
RATE (mm/day) 200-400 200-300 <70 0.1-1 2-8
CARGO Golgi-derived Vesicles Endocytic Mitochondria Intermediate filaments


PRIMARY FUNCTION Membrane maintenance Return molecules destined for degeneration back to the soma ATP production

Specific site metabolism maintenance Aerobic metabolism, calcium homeostasis and cell death

Transport newly synthesised cytoskeletal proteins for axonal growth and regeneration

Fast Axonal Transport

Fast axonal transport is characterised by the bidirectional movement of membranous structures at fast rates - up to at least 70mm/day [20] . It can further be divided up into another three components based on the type of vesicular cargo, direction of movement, and overall rate of movement. The transport of mitochondria has been classified within its own component due to its unique movement and functions. Additionally, structures that have common functions and high levels of interaction are likely to be transported together in a bulk flow of movement[21] .

<mediaplayer>https://www.youtube.com/watch?v=KWM0SOwg9k0</mediaplayer> This video demonstrates the fast axonal transport within the axon of a giant squid via video-enhanced contrast-differential interference contrast microscopy. Transport of membranous materials can be seen moving in both anterograde and retrograde directions with little to no frequent pauses.

Fast Retrograde Transport

Slow retrograde transport functions in returning molecules from the axon back to the soma. These materials include trophic factors, exogenous materials and old membrane constituents, and travel at rates between 200-300mm/day[22]. They are bound to dynein motor proteins due to the fact that they’re traveling towards the minus ends of the microtubules.

Generally, the membrane bound organelles traveling in retrograde movement are structurally larger in size[23]. Also, the cargo in retrograde transport are mainly composed of different types of cells, as compared to cargo in anterograde transport that are specifically sorted and packaged into appropriate cargo based on similar structure and functions. However, there is coordination between the two components: fast and slow anterograde transport delivers membranous and cytoskeletal proteins, respectively, whilst retrograde transport will return them back to the soma in a soluble form [24]

The primary function of retrograde transport is to return molecules destined for degradation to lysosomes within the soma, preventing accumulation of old molecules in the axon which may cause neuronal dysfunction [24]. Additionally, retrograde transport returns exogenous products of endocytosis from the distal axon, ensuring neural survival and regulation of gene expression [23]

Fast Anterograde Transport

Fast anterograde axonal transport is characterised by the rapid movement of golgi-derived veriscles along the axon in the anterograde direction. Materials are synthesized in the cell body of the soma, bound to dynein and then travel along the plus ends of the microtubule tracks at approximate rates from 200-400mm/day[25]

Many types of membrane-associated organelles and materials are transport at fast rates in the anterograde direction. These include enzymes, neurotransmitters, neuropeptides and membranous lipids. Essentially, they are all produced in the cell body, however some materials such as membranous proteins must first undergo processing and sorting before transport.

Newly synthesized membrane proteins and secretory proteins are classified as Golgi-derived vesicles because they must first pass through the Golgi complex before packing, or associate with proteins that do [11]. Synthesis and packaging of these proteins happen within the soma. The Golgi apparatus within the cytoplasm receives newly synthesized integral membrane and secretory proteins from RER. These proteins are then modified, sorted and packaged appropriately before its attachment to dynein, the motor protein responsible for anterograde movement [26].

The materials transported by fast anterograde transport perform many various functions, as compared to slow anterograde transport, which strictly carries cytoskeletal proteins for maintenance of axonal growth and survival. Membrane and secretory proteins are transported to functionally heterogenous domains within in the axon, such as presynaptic terminals, axolemma and nodes of Ranvier. At these various locations, these membrane-associated proteins function to maintain axonal metabolism, and must therefore be continuously and efficiently be transported at fast rates.

Fast Axonal Transport of Mitochondria

Like cytoskeletal polymers, membranous organelles and other materials transported by axonal transport, mitochondria primarily arise from the soma. However, mitochondria present distinct features in their movement along the axon, classifying them under their own rate component in axonal transport. They are distinct in their overall net rate speed, direction of movement and number of pauses.

The mechanisms underlying the axonal transport of mitrochondria are generated by fast motors, allowing it to transit up to speeds of up to 70mm/day. However, this is still unusually slow compared to the other components of fast axonal transport, whereas fast anterograde movement averages between 200-400mm/day and fast retrograde movement generally travels between 100-250mm/day[27].

Furthermore, transport of mitochondria is defined by its saltatory and bidirectional movement within the axoplasm[28]. Under observation, mitochondria has been seen to have many frequent pauses, unusual for fast transport, but common in slow transport (PMID: 8314882). Additionally, they will frequently change direction during movement, switching between anterograde and retrograde movement. The shifting between moving and stationary states are the results to changes in axonal growth and intracellular signaling[29].

Mitochondria is also distinct in its overall functions regarding the neuron. A defining characterisic of mitochondria is its ability to sequester factors of apoptosis , buffer cytosolic calcium and produce ATP [30]. Due to its unique roles, mitochondria is needed across different locations along the axon, therefore resulting in the continuous starts, stops and change in direction during its transit. Mitochondria is not simply delivered to specific sites to fulfill cell needs, but must continually be repositioned to accommodate for the complex requirements of the neuron; particularly in aerobic metabolism, calcium homeostasis and cell death[31] Mitochondria is also unique in its interaction with different cytoskeletal networks in which it functions to control cytoskeletal morphology, movement and anchorage within the cells [32]

<mediaplayer>https://www.youtube.com/watch?v=3eseW37WDAQ</mediaplayer> The complex movement of mitochondrial transport: many frequent pauses with bidirectional movement

Slow Axonal Transport

Non-membranous structures including cytoskeletal polymers (neurofilaments, microtubules and intermediate filaments) and other cytosolic protein complexes strictly transport along the axon at overall slow rate - via slow axonal transport [33] . Growth and elongation of axons primarily occur at the plus ends of microtubule track; therefore, slow axonal transport only occurs in the anterograde direction. This enables motor proteins to transfer newly synthesized proteins from the soma to specific destinations along the lengths of the axon[34]. The continual transportation and delivery of these proteins allows the cytoskeleton to adapt to the dynamic nature of the neuron. Since they are continually changing in length and shape, the polymers of the cytoskeleton are always being renewed due to axonal transport.

<mediaplayer>https://www.youtube.com/watch?v=Ubz9YG-h18w</mediaplayer> This video shows slow axonal transport responding to neuron growth - delivering newly synthesised cytoskeletal polymers to adapt to the changes in length.

Rate Components: SCa and SCb

There are two distinct rates of transport occurring within slow transport: slow component a (SCa) and slow component b (SCb). These two subdivisions of slow transport are characterised by their rate of transport, again, dependent on the type of protein that is being carried[35]. In regards to cytoskeletal proteins, intermediate filaments and microtubules are transmitted under SCa rate components at approximately 0.1-1mm/day, whilst microfilaments travel under SCb rate components at approximately 2-8mm/day[36].

Fast Mechanisms of Slow Transport

It was previously believed that fast and slow transport operated under unique mechanisms. However, exploiting sympathetic neurons in culture into which plasmids encoding GFP-tagged NF-M were microinjected to allow live cell observations. Observations of the photo bleached fluorescent neurofilaments showed many long pauses, however, when anterograde movement occurred, it would be at 2mm/day. This significantly resembled the anterograde speeds that occur during fast transport. It was therefore concluded that slow axonal transport functions under the same mechanisms as fast transport, with the exception that fast motors in slow transport have many frequent pauses during its transit[37][38].

Due to the discovery that fast and slow anterograde mechanisms of movement are both generated by fast motors, revised methods of measurement have been applied in order to define and differentiate overall net rate of transport. [1]. A unified perspective in measuring the net rate velocity of transport takes into consideration both the time spent in a stationary position (pauses) and the actual time spent movement throughout the entire course of transport. For example, a structure moving at speed of 5micrometres/second, but only spends 1% of that time actually moving (1 second of movement in every 100 seconds), then its average net rate velocity will translate into 0.05 micrometres/second. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171826/)

Functional Significance

The functional significance of axonal transport is summarised here:

  • Growth and regeneration of a nerve is significantly dependent on the processes of slow, anterograde axonal transport in its delivery of newly synthesized proteins. The rate of axonal growth during development and regeneration of a nerve is approximately equivalent to the rate of SCb within that neuron [2]. This highlights the importance of axonal transport in the overall growth and survival of a neuron, and without these mechanisms, axons may fail to reach optimum function and thus cause severe disorders.
  • The cytoskeletons that comprise the axonal architecture are highly dynamic - continuously changing in shape and size to accommodate for essential functions of neurons. These proteins must be actively renewed to maintain optimum function. Therefore, slow anterograde axonal transport delivers newly synthesized to required destinations at efficient times as an adaption to the ever-changing nature of the axon.
  • Axons have the capacity to extend for great distances, but they lack necessary local components within the axoplasm for protein synthesis. However, recent studies have identified mRNA translation within the axon, but in limited forms [39]. Therefore, in neurons, the soma is the primary site of protein synthesis, achieved by the functions of Nissl substance, rough endoplasmic reticulum (RER) and free ribosomes. The distance between site of production and target destination can extend a great length and proteins cannot independently travel these distances. Fortunately, mechanisms of axonal transport and motor proteins allow essential materials to travel significant distances.
  • Transport of mitochondria is essential in the production of ATP energy used by motor proteins to travel along the axon. Without sufficient energy provided by mitochondria, the overall processes of axonal transport would be strictly limited in speed, consequently reducing metabolic functions of the neuron. Additionally, axonal transport allows mitochondria be continually repositioned by frequently pausing and changing direction during its transit along the action. This is influenced and controlled by changes to axonal growth and intracellular signalling. Finally axonal transport allows mitochondria to fulfil its roles of aerobic metabolism, calcium homeostasis and apoptosis.
  • If there is a build up of degenerated molecules along the lengths of the axon, it will cause many functional disorders. Fast retrograde transport delivers molecules destined for degradation to the cell body. Furthermore, retrograde transport returns materials back to the soma for repackaging or gene regulation.

Motor Proteins

Kinesin Dyein
Structure Two heavy chains wound together in a coiled structure and two light chains Two or three heavy chains with multiple and intermediate light chains
Direction of Movement Anterograde - Proteins are synthesised in the cell body and transport down the axon to the synaptic terminal Retrograde - Proteins at the synaptic terminal are transported back to the cell body for degradation and recycling


The Role of Kinesin and Dynein in Powering Axonal Transport



Ribbon Diagram of The Structures of Kinesin

Kinesin is composed of two 115-kD kinesin heavy-chains (KHC) and two 58-kD kinesin light-chains (KLC) subunits encoded by single-copy genes. It plays a significant role in powering anterograde axonal transport in which the microtubule motor activity is performed by the heavy chains of kinesin - The function of light chains of are poorly understood in this process. [41] Some kinesins are monometric, comprising of a single heavy chain, however most are dimetric. Due to differences in structure, these two types of kinesin may move along microtubules by different mechanisms. [40]

Kinesin's comprise of a motor domain, a copied domain and occasionally, a gene-specific domain. They all belong to a family of related motor proteins in which they all contain the kinesin motor domain, but they differ in their tail domains and other properties. [42] The motor domain is located centrally (M-type), located at the N-terminus (N-type), or at the C-terminus (C-type). [40] Both M-kinesins and N-kinesins possess a plus end-directed motility towards the axon terminal allowing for anterograde transport. These are responsible for both fast and slow transport. C-kinesins reflect their mircotubules minus end-directed motility, thus assist dynein in retrograde transport.[42]


Kinesins use microtubules to transport cargo along with the chemical energy of ATP to drive structural changes that generate motile. It is significant in allowing various membrane organelles and protein complexes to be transported bidirectionally to control neural functions. [42]

Fast axonal transport operates at a similar speed of Kinesin motors in vitro being 20-300mm per day, where as slow axonal transport performs at a rate of 0.1-3mm per day. As N-kinesins are responsible for fast and slow transport, the difference between the speed of fast and slow axonal transport has not been full explained.[42]

The Role of Different Kinesins:

  • KIF1A and KIF1Bβ bind to RAB3 proteins through the adaptor protein mitogen-activate protein kinase (MAPK)-activating death domain and are responsible for transporting synaptic vesicle precursors that contain synaptic vesicle proteins, such as synapotophysicm, They are incapable of transporting organelles that contain plasma membrane proteins such as syntaxin 1A. Similar to KIF1Bα, and KIF13B, they only facilitate anterograde transport in axons. [42]
  • The kinesin 3 family motor KIFB and the KIF5 motors are thought to be involved in the transport of mitochondria along the axon. KIF1Bα is associated with mitochondria and can be transport in vitro. Current research suggests the KIF1B binding protein is localised to mitochondria and its removal results in mitochondrial aggregation. Similarly, when the KIF5 gene is disturbed in mice, mitochondria gathers in the centre of the cells suggesting its significance in mitochondrial transport. [42]
  • KIF3A and KIF3B (kinesin 2 family motors) exist in a heterotrimeric KIF3 motor complex along with the KIF-associated protein 3 (KAP3). These kinesins are essential in axonal elongation. Fodrin-associated vesicles are transported by the KIF3 motors providing plasma membrane components to the tips of neurites. Furthermore, binding of DISC1 (scoffold protein disrupted in schizophrenia) to KIF5 motors enables the axonal transport of nudel and lisencephaly 1(LIS1) which are necessary for axonal elongation. [42]
  • KIF5 proteins are known to be generally fast motors, although it has been demonstrated they can also contribute to slow axonal transport. It was found they were capable of slowly transporting tubilin dimers using the adaptor protein CRMP2, which directly bound to the TPR domain of KLC1. The mechanisms that allow KIF5 are not yet understood.[42]

Mechanisms of Movement

1. Hand-Over-Hand Model: Predicts that for each ATP hydrolysed, the rear head moves twice the centre of mass, whereas the front head does not translate. When one head of kinesin was dyed, the heads were demonstrated to past one another, altering the position of the kinesin head in front. In the symmetric version of the hand-over-hand model, the stalk was thought to rotate 180 degrees in comparison to no rotation in the asymmetric model.

2. Inchworm Model: Predicts a uniform translation of 8.3nm for all part of the motor, which is equal to the centre-of-mass translation. In this method, the stalk does not rotate during a step. [43]

Kinesin "Walking" Along A Microtubule <mediaplayer>https://www.youtube.com/watch?v=LUtV7VV2Yuc</mediaplayer>


Dynein was originally identified 50 years ago as an ATPas in Tetrahymen pyriformic cilia. Consequently, a cytoplasmic form of dyenin was isolated from brain tissues and demonstrated to drive intracellular transport towards the negative ends of microtubules. The discovery of dynein complemented the finding of kinesins. [44]


Live Cell Imaging of Cytoplasmic Dynein

Dyneins are extremely large multimeric proteins composed on two or three heavy chains complied with an unidentifiable amount of intermediate and light chains. Each heavy chain contains a motor domain belonging to the AAA+ superfamily attached to a divergent amino-terminal tail domain. The tail serves as a platform for the binding of different associated subunits which mediate interactions with cargo via direct biding or through the recruitment of adaptor proteins. Dynein exists in two forms including cytoplasmic dynein and axonemal dynein. Cytoplasmic dynein is characterised by a two-headed motor as it assembles around two identical heavy chains. Five classes of additional subunits including the intermediate chain, light intermediate chain and three types of light chain determines their function. Furthermore, cytoplasmic dynein interacts with three regulators consisting of lissencephaly 1, nuclear distribution and the dynamic complex. The role of these regulators is to differ the intrinsic mechanisms of cystoplasmic dynein. [44]


Cytoplasmic dynein moves membranous organelles from the distal regions of the axon to the cell body. This is axonal transport in the retrograde direction, towards the minus ends of microtubules. Research conducted on mouse saphenous nerves has found cytoplasmic dynein associated with membrane organelles moves in both directions. It was suggested inactive dynein is transported to the nerve terminal of anterogradely moving membranous organelles by kinesin.[45]

Cytoplasmic dynein is the motor for retrograde fast axonal transport of membrane organelles from the synapse to the cell body.[46] Because dynein is synthesised in the neuronal cell body and therefore must be transported to the axon terminal. Research conducted on mouse saphenous nerves has found cytoplasmic dynein associated with membrane organelles moves in both directions. It was suggested inactive dynein is transported to the nerve terminal of anterogradely moving membranous organelles by kinesin in the slow form.[46] This movement is thought to represent bulk transport of inactive dynein into the synapse for eventual use as the motor for retrograde transport. It binds to microtubules in at ATP dependent manner in vitro suggesting the slow component b complex (SCb) dynein is functionally active, supporting the evidence inferring dynein is the motor for slow axonal transport. [45]

Examples of Organelles Trafficked by Cytoplasmic Dynein:

  • Endosomes
  • Lysosomes
  • Phagosomes
  • Melanosomes
  • Lipid Droplets
  • Mitochondria

Transport of these organelles are essential in transmitting signals between various aspects of the cell. At nerve terminals, stimulated tropomyosin-receptor kinase (TRK) receptors endosomes are transported by dyneins towards the cell body, where signalling cascades are initiated necessary for neuron survival. [44]

Mechanisms of Movement

The motor domain of dynein consists of a carboxy-terminal region in the heavy chain which contains the components necessary to convert the energy from ATP hydrolysis into movement. This process is thought to occurs through a mechanochemical cycle.

The Mechanochemical Cycle: [44]

1. ATP induces dissociation of the motor-microtubule complex

2. The motor detaches from the microtubule

3. The motor rearranges becoming primed for a structural change (power stroke) that is thought to generate force

4. The motor undergoes a diffusive search and binds to a new site on the microtubule

5. This stimulates the release of ATP hydrolysis products

6. The power stroke is triggered

Dynein Movment Along a Motor Protein <mediaplayer>https://www.youtube.com/watch?v=v4bqgaRvqMI</mediaplayer>


The Structure of Dynein and Dynactin


Dynactin is a multisubunit protein complex appearing as a short filament 37nm in length with a thinner laterally orientated filament that separates in two globular heads.[47]. It contains two structural domains consisting of a projecting sidearm that interacts with dynein and an actin-like mini filament backbone that is bound to cargo. When dynactin was combined with chaotropic salt and potassium iodine, it was discovered multiple protein complexes existed. The shoulder/sidearm complex represents a similar structure to dynactin’s projection sidearm containing p150glued, dynamitin and p24 subunits. The shoulder complex consists of a elongate and flexible arrangement containing dynamitin and p24. It is though to link the shoulder/sidearm complex to the Arp1 minifilament. Lastly, the pointed-end complex is made up of p62, p27 and p25 subunits containing cargo binding devices and Arp11, an actin-related protein determining its pointed-end capping activity. [48]


Research suggests dynein and dynactin work together to carry out dynein functions. Previously it was thought only highly purified dynein could mediate vesicle attachment to microtubules in the absence of dynactin. It has now been determined hat the attachment of dynein to membrane vesicles requires dynactin, although some controversy still exists with dynein light and intermediate chain subunits being thought to link dynein to other membrane proteins without dynactin. However, through all the evidence it can be concluded the primary role of dynactin is to regulate and coordinate the functions of dynein with a significant aspect in its processing. With further investigation, it was found that dynein interacts with the dynactin complex through binding of dynein intermediate chains to the p150 glues subunit of dynactin.[49]

Dendritic Transport

As mentioned in axoplasmic transport, proteins and organelles are transported by the microtubule motors dynein and kinesin[50]. This according to much research doesn't really change for dendritic transport. A starting point on where the two transport systems change is actually at the microtubules. Dendritic microtubules are of mixed polarity compared to the uniformity of axonal microtubules[51]. Research shows this difference in polarity may influences the general movement of organelle traffic patterns[51]. Not only does the polarity affect organelles, proteins also differ in how they are transported along the dendrite. There are currently many different models that speculate as to the exact mechanism of transport for proteins and organelles in dendrites. This highlights the need for more research to be done on this area to create a unified theory.


One such mechanism that looks at the transport of proteins is by Ramírez OA, Härtel S, Couve A[52]. They suggest a few different models on proteins trafficking. One model begins at the soma. The post-Golgi secretory vesicles travel from the soma along microtubules with the help of motor proteins. A recycling endosome processes the vesicle and unloads the receptor at the post synaptic density of a dendritic spine.

Model for mRNA translation in neuronal dendrites by Bramham C.R, Wells D.G[53].

Depicted in the same figure[52] they provide is another more complex mechanism involving endoplasmic reticulum. Also beginning at the soma, rough ER transitions to become smooth ER in the dendrite. The protein enters the ER network at an endoplasmic reticulum exit site and exits at the dendritic endoplasmic reticulum exit site. On exiting the protein move towards a Golgi outpost where they are eventually inserted via vesicles to the membrane of the dendritic spine. Combined with other research they have done in this area, Ramírez OA, Härtel S, Couve A suggest a important relationship between ER and the trafficking of proteins along the dendrite.

On a smaller level the transport of mRNA is also disputed in different research. The consensus is mRNA is transported via large ribonucleoprotein particles. Where Bramham C.R, Wells D.G [53] differ in their research is they suggest mRNA is inhibited via transportation by an mRNA binding protein. It then still goes along the microtubule path with kinesine being the motor protein. When there is synaptic activation, the mRNA binding protein travels via an actin-based myosin motor protein towards the activation where it is neutralised and mRNA is able to synthesis new protein. This process is visualised via the diagram to the right.

Hirokawa N.[54] suggests a different theory. These many different types of research only highlight how little we know about dendritic transport and the mechanism that drive it.

Diseases and disorders

Mutations in kinesin and dynein, motor proteins, have been found to have a casual nexus to triggering multiple rare neurodegenerative diseases. The primary means in which these cases are facilitated is through axonal and dendritic transport.

Axoplasmic disorders

Alzheimer’s diseases

Sporadic neurodegenerative diseases such as Alzheimer’s have been caused by deficits in axoplasmic/axonal transport. Alzheimer’s disease is a type of neurodegenerative dementia, characterised by cognitive decline including a progressive loss of memory, orientation and reasoning.[55] Axoplasmic transport of neurotrophic factors (NTF) in Alzheimer’s disease are crucial as many of these proteins do not synthesise at their specific actions sites.[55]

Alzheimer’s neurodegeneration is characterised, by neuropathological changes and deposits of misfolded proteins. Firstly due to the hyperphosphorylation of Tau proteins in neurofibrillary tangles and secondly due to amyloid-β(Abeta) deposits in cerebral blood vessels. [55] Tau proteins act as promoters of tubulin polymerisation. In Alzheimer’s disease, there is a direct link between hyperphosphorylation, abnormal phosphorylation and Tau aggregation, facilitated by axonal transport. Tau protein phosphorylation occurring internally and externally from the microtubule binding domains significantly affects the tubulin formation and assembly, by altering the affinity between Tau and microtubules.[55]

Similarly amyloid-β(Abeta) is suggested to be a vital cause of dysfunction and neuronal loss. These processes are enabled by a series of events in the axon comprising of the “generation of free radicals, mitochondrial oxidative damage and inflammatory processes.”[55] Abnormal accumulation of Abeta is primarily linked to the “dysregulated proteolytic processing of the amyloid precursor protein (APP).”[56] Abeta aggregation has been distributed by anterograde axoplasmic transport plaques [57] [58] On the other hand there are studies that support the theories that Abeta may also damage axonal transport, through “oligomeric Abeta42 in microtubule-associated endosomal vesicles”[59]


It’s not surprising that main vehicle facilitating the distribution of major proteins involved with Alzheimer’s disease is axoplasmic transport. There has yet to be a definitive therapy that is able to treat Alzheimer’s disease. Although studies have been able to determine the hyperphosphorylation of tau protein and the relationship between APP, there is still no cure for Alzheimer’s disease.[55] Current therapies, once diagnosed, are either of a pharmaceutical, psychological and caregiving nature. There is an emphasis placed on preventative measures such as lifestyle, diet and genetic test to determine hereditability and was of minimising the effects of Alzheimer’s.

Pharmaceutical options unfortunately provide minimal benefit with their use. There are five medications that are available such as memantine NMDA receptor antatgonist and acetylcholinesterase inhibitors ranging from (donepezil, galantamine, tacrine and rivastigmine).[60] Psychological interventions are only implemented in association with pharmaceutical options. They include behavioural, cognitive, emotional and stimulation-oriented methods.[61]

The primary treatment is caregiving, due to the progressive degenerative nature of Alzheimer’s disease the degree of care provided varies. In the early stages adjustments in lifestyle and environment are implemented. They vary from to simplifying daily routines to even labelling household items to trigger the patient.[61] [62] Unfortunately as the disease progresses patients develop different medical problems may arise like malnutrition, hygiene problems, oral and dental disease to name but a few. Although in the final stages palliative treatment is administered to minimise any discomfort.[63]

Unraveling the Mystery of Alzheimer's Disease <mediaplayer> http://www.youtube.com/watch?v=NjgBnx1jVIU</mediaplayer>

Alzheimer’s Disease: 3D Health Animation <mediaplayer> http://www.youtube.com/watch?v=y3g4emLQ1Ic</mediaplayer>

Wallerian Degeneration

Flouresecent microscope image of damage to axons through Wallerian degeneration. (A), (B), (E), (F) show time lapse and comparison of cut injury in proximal and distal part of the axon. (C), (D), (G), (H) show time lapse and comparison of crush injury in proximal and distal part of the axon. [64]

Properly functioning axons rely on axonal transport for maintenance through vital proteins and materials. If an injury were to disrupt such a process, it would have significant effects on the axons ability. Wallerian degeneration, also referred to as anterograde degeneration, is a process that results in deterioration to the distal part of an axon and is caused either via an impaction on the axon or a lesion, eventuating in complete fragmentation to the axon [65] The rate of degradation is dependent on the type of trauma sustained by the axon and the diameter of axons, it takes longer to disintegrate larger axons.

Injuries in the axon initiate acute axonal degeneration (AAD), a quick process (within 30 minutes of injury) whereby the proximal part of the axon (part nearest the cell soma) rapidly separates from the distal end. [66] Followed by the inflammation of the axolemma, eventuates into a beading formation and degradation. After the axolemma is compromised granular disintegration of the axonal cytoskeleton and inner organelles occurs. This results in mitochondria inflammation and disintegration. Properly assembled microtubules are essential to maintain axoplasmic transport processes, once depolymerisation of microtubules arises, it stimulates degradation of the neurofilaments and other cytoskeleton components. This disintegration is an active process dependent on Ubiquitin and Calpain proteases (caused by increase of calcium ion). [67]

Dendritic Disorders

Dendritic abnormalities are most commonly attributed to mental retardation, primarily through dendritic spine dysgenesis. There have been direct correlations with obvious cases of dendritic abnormalities of branches and/or spines between genetic disorders such as Down, Rett and fragile-X syndromes. There have also been preliminary studies that propose, through cytoarchitectronic analyses, that dendritic abnormalities play a role in Williams and Rubinstein-Taybi syndromes.The below table covers neocortical cytoarchietecture and dendritic abnormalities in genetic disorders associated with mental retardation. [68]

Neocortical cytoarchietecture and dendritic abnormalities in genetic disorders associated with mental retardation [68]
Disorder Laminar Disturbance Increased Packing Density Reduced Length Spine Dysgenesis
Down Syndrome Yes No Yes Yes
Fragile-X syndrome No No No Yes
Patau syndrome No No Yes Yes
Tuberous sclerosis Yes (focal) Yes (focal) Yes (focal) Yes (focal)
Williams Syndrome Yes No ? ?
Rett Syndrome No Yes Yes Yes
Rubinstein-Taybi syndrome No Yes ? ?

Dendritic disorders manifest themselves through syndrome-specific changes in early development and evolution, drawing a causal link between its cognitive profile. There are two main abnormalities that characterise dendritic disorders these include reductions in the length and abundance of branches and the irregular formation of dendritic spines. Theses mutations primarily occur in the pyramidal neurons, where both apical and basilar branches are shorter and have a simpler morphology and the dendrite spines are long and thin, immature growth results in spine dysgenesis. [68]

Flouresecent microscope image of damage to pyramidal neuron dendrite growth. (A) and (B) show regular dendrite branching with no overexpression of MeCP2. (C) and (D) show over expression effects of MeCP2 on dendrite branching [69]

Rett Syndrome

A neurodevelopmental disorder that predominately affects females through a mutation in the X chromosome gene MeCP2. MeCP2 mutations alter functional domains in proteins. Whilst perinatal development is normal in Rett Syndrome what follows is complications in neurological and physical components. These include regression of language and motor skills, the onset of seizures and appearance characteristic stereotypic movements. [68] Dendritic arborisations significantly reduce function in the premotor, motor and inferior temporal cortices. [70]

Treatment and Future Studies

There is currently no definitive cure for Rett Syndrome yet studies have concluded that by restoring MeCP2 function perhaps there is potential to treat and provide possible therapy. There are various treatment methods ranging from pharmaceutical selective serotonin reuptake inhibitors, to occupational, speech and physical therapy, to management of nutrition and surveillance of onset of scoliosis measures and even counselling session for both the patient and the parents.

There is hope in a cure through studies having demonstrated that if gene function is repaired, MeCP2 neurological deficits effects can be restored. When Mecp2 is administered gradually and in the correct spatial distribution functionality can be regained. Although this is a positive step towards treatment, further research must be undertaken to identify the specific molecular mechanisms underlying individual Rett Syndrome phenotypes. To determine which of these candidates are viable to be therapeutically treated. [71]

Future studies must be geared towards assessing the level of recovery attainable by these treatments. The subtler determinates of MeCP2 in Rett syndrome must also be recovered when protein function is restored postnatally. [71]

Current and Future Research

Current studies in axoplasmic and dendritic transport have been to determine conclusively the mechanisms that promote directionality in axons and dendrites. This is a crucial factor in being able to further our understanding of the behaviour of motor proteins and why they follow either a dendritic of axonal pathway.

Studies have also been undertaken in the disorders that lead to cognitive deficiencies and whether or not they are directly associated with axoplasmic or dendritic transport. Researchers investigated diabetic encephalopathy, a cognitive deficit brought on by diabetes mellitus, to observe if axoplasmic transport interruptions affected the nervous system. Results showed an overexpression of KIF1A and KIF5B in the hippocampus, yet dynein expression remained constant. The study concluded that anterograde axonal transport, facilitated by these kinesins, inhibits neurotransmissions on hippocampal neurons, leading to cognitive and memory impairments in diabetes-associated disorders. [72]

Further research needs to consolidate what has been done so far and provide a strong unified theory as to the exact mechanisms. Yet what is most pivotal in pioneering the next frontier in axoplasmic and dendritic transport research is that for sustainable treatment therapy.


Acetylcholinesterase inhibitors: Primary medication used to treat suffers of Alzheimer’s disease. It a chemical that hinders acetylcholinesterase enzyme from breaking down neurotransmitter acetylcholine, thus increasing both the level and duration of action of the acetylcholine. [73]

Acute axonal degeneration (AAD): a quick process (within 30 minutes of injury) whereby the proximal part of the axon (part nearest the cell soma) rapidly separates from the distal end.

Alzheimer’s disease: type of neurodegenerative dementia, characterised by cognitive decline including a progressive loss of memory, orientation and reasoning. [74]

Amyloid-β(Abeta): peptides containing 36-43 amino acids are a product of amyloid precursor protein cleavage. They are primary component of amyloid plaques

Amyloid Precursor Protein (APP): internal membrane protein expressed and concentrated in the synapses of neurons 16822978

Calpain proteases: calcium dependent proteolytic enzyme

Granular disintegration: cell deterioration process

Hyperphosphorylation: biochemical with multiple phosphorylation sites is fully saturated

Neurofibrillary tangles: accumulation of hyperphosphorylated Tau proteins. These are a key marker in Alzheimer’s disease

MeCP2: methyl CpG binding protein 2 part of X gene that is effected in Rett Syndrome

Pyramidal neurons: type of neuron specifically located in the hippocampus, amygdala and cerebral corted

Rett Syndrome: neurodevelopmental disorder that predominately affects females through a mutation in the X chromosome gene MeCP2

Tau proteins: protein involved in the stabilisation of microtubule function

Ubiquitin: regulatory protein located in the majority of tissues

Wallerian degeneration: in deterioration to the distal part of an axon and is caused either via an impaction on the axon or a lesion, eventuating in complete fragmentation to the axon [65]

Mitogen-Activate Protein Kinase (MAPK): Serine/threonin, tyrosine-specific protein kinases belonging to the CMGC kinase group [75]

Synnaptotophysicim: The major synaptic vesicle protein p38, is a protein that in humans is encoded by the SYP gene [76]

Syntaxin: A family of membrane integrated Q-SNARE proteins participating in exocytosis [77]

Fodrin: Provides the general linkage system between microfilaments and the membrane in nonerythroid and non muscle cells [78]

Nudel: Nuclear distribution protein that is encoded by the NDEL1 gene [79]

Axonal Elongation: Tip growth in which new material is added at the growth cone while the remainder of the axonal cytoskeleton remains stationary [42]

AAA+ Superfamily: ATPases Associated with diverse cellular Activities - AAA proteins couple chemical energy provided by ATP hydrolysis to conformational changes which are transduced into mechanical force exerted on a macromolecular substrate [80]

Tropomyosin-Receptor Kinase (TRK): A family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system [81]

Axon: long, cylindrical process of the neuron. Axonal transport occurs within the axon.

Axoplasm: cytoplasm within the axon

Cytoskeleton: cellular scaffolding of the axon. Composed of microtubules, microfilaments and intermediate filaments

Fast transport: transport of membranous cargo at speeds of 200-400mm/day

Golgi apparatus: intracellular organelle responsible for the appropriate sorting and packaging of membranous molecules before transport

Golgi-derived vesicles: consisting of membranous proteins and secretory proteins. Transported under fast anterograde transport

Intermediate filaments: or microfilaments. Protein component of axonal cytoskeleton with branching capabilities.

Membranous structures: composed of endocytic and golgi-derived vesicles and mitochondria. Form the cargo of fast transport.

Microtubules: protein component of the axonal cytoskeleton. Form tracks for the process of axonal transport

Mitochondria: primary site of ATP production in the neuron. Transported at speeds <70mm/day

Neurofilaments: protein component of the axonal cytoskeleton. Composed of actin.

Non-membranous structures: cytoskeletal and cytosolic proteins transported by slow axonal transport.

Retrograde transport: movement of cargo towards the minus ends of the microtubule, or towards the soma.

SCa: Slow component a, of slow axonal transport. Transports intermediate filaments and microtubules at 0.1-1mm/day

SCb: Slow component b, of slow axonal transport. Transports microfilaments at 2-8mm/day

Slow transport: anterograde movement of cytoskeletal and cytosolic polymers, ranging between

Soma: the neuron cell body. Primary site of synthesis for materials of axonal transport.


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