Neurological conditions such as motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease have many overlapping disease mechanisms.
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These include oxidative stress, neurodegeneration, protein aggregation, mitochondrial dysfunction, and microtubular transport impairments. In this article, microtubular transport in neurons will be discussed, how they are implicated in disease, and how molecular motors can be used to potentially treat neurological conditions.
What are Microtubules and Molecular Motors?
Each cell has a network of microtubules that form part of the cytoskeleton to provide structure to cells, including neurons, and are dynamic structures that assemble and disassemble depending on the cellular processes that are occurring, including providing a scaffold for intracellular transport (of cargo and organelles).
Microtubules are formed by the polymerization (stitching together) of alpha and beta-tubulin forming hollow tubes.
Molecular motors are involved in the movement of cellular components by utilizing free energy (hydrolysis of ATP) to provide mechanical force. Acting on microtubules, there are 2 key types of molecular motors (cytoskeletal motors): kinesin (comprising of KIFs) and dynein (DHCs).
Acting on actin filaments, myosin is another molecular motor. Molecular motors bind to their cargo through adaptor proteins forming protein complexes.
Kinesin is involved in anterograde transport along microtubules (moving cargo away from the nucleus) whereas dynein is involved in retrograde transport (towards the nucleus) as well as in the movement of cilia and flagella.
Neurons are polarised cells that comprise of dendrites leading towards the cell body and axons, which can be very long and move away from the cell body.
Synaptic and axonal proteins need to be transported from the cell body down to the axon terminal/synapse, whereas in dendrites, specific mRNA is transported, and protein synthesis occurs locally (such as CaMKIIa, Arc, and Fmr1).
Intracellular transport is therefore absolutely crucial for neuronal function and survival. Within synaptic regions, the filaments are mainly actin therefore the main molecular motor here is myosin. Axonal and dendritic transport is bidirectional and is carried out by kinesin and dynein.
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Molecular Motors in Treating Neurological Disorders
Specific mutations to components of molecular motors are implicated in several neurological conditions. For example, mutations to Kif5a (affecting Kinesin-1) is implicated in spastic paraplegia (SPG10).
Mutations to Kif1a (Kinesin-3) lead to Charcot-Marie-Tooth syndrome. Kif1b mutations can lead to multiple sclerosis. Myosin defects are predominantly associated with hearing loss/deafness (e.g. Myo1a). Amyloid precursor protein (APP); implicated in Alzheimer’s disease is carried by KIF5, and mutations to KIF5 impair APP transport.
Bidirectional movement within cells can sometimes encounter a ‘roadblock’ and can switch polarity to ‘turn-back’ in the opposite direction. Consequentially, the net movement of a particular cargo determines the overall location within a cell, and KIF1C can transport bidirectionally by cooperating with dynein.
A recent study by Siddiqui and colleagues (published in Nature Communications) investigated the mechanisms behind KIF1C bidirectionality that switch KIF1C transport on and off. Their findings describe a model in which KIF1C is normally autoinhibited by being a stable dimer by the interaction of its stalk region which contains its microtubule-binding domain (therefore switched “off”).
Binding of a protein called PTPN21 or Hook3 changes conformation (shape) of KIF1C to expose its binding domains, thereby allowing it to bind to microtubules and act as a molecular motor in the transport of cellular cargoes, increasing binding by 40%.
Furthermore, PTPN21 was able to compensate for the lack of KIF1C (inhibited) by activating another protein called KIF16B (endosome transporter) to allow the continuation of microtubular transport of KIF-associated cargoes.
PTPN21 promotes neuronal survival and growth, and specific mutations are associated with schizophrenia. Thus with the knowledge of the exact mechanisms underlying KIF1C activation and directionality, further research may be able to alleviate microtubular dysfunction in several implicated neurological conditions, such as by using PTPN21 or Hook3 as a therapeutic agent in cells that lack normal KIF1C function.
In summary, molecular motors are crucial to the transport of proteins, RNA, organelles (cargoes) by providing the mechanical force needed to push cargoes along microtubules within cells, especially in neurons that often have long axons.
Specific mutations to these molecular motors (such as dynein and kinesin) are implicated in several neurological conditions including hereditary spastic paraplegia (HSP). Recent evidence has suggested a mechanism by which specific kinesins can be activated, such as PTPN21 binding to KIF1C to allow transport, and this could be used as a potential therapeutic strategy to allow the continuation of cargo delivery within neurons in the treatment of conditions such as HSP.
- Shliwa & Woehlke, 2003. Molecular motors. Nature. 422(6933):759-765 DOI: 10.1038/nature01601
- Hirokawa et al, 2010. Molecular Motors in Neurons: Transport Mechanisms and Roles in Brain Function, Development, and Disease. Neuron. 68(4):610-38. DOI: 10.1016/j.neuron.2010.09.039
- Siddiqui et al, 2019. PTPN21 and Hook3 Relieve KIF1C Autoinhibition and Activate Intracellular Transport. Nat Commun. 10(1)2693. DOI: 10.1038/s41467-019-10644-9