Tag Archives: motor proteins

Drosophila helps understand axonal transport

The roles and regulations of the neuronal cytoskeleton are complex. Simple genetic model organisms such as Drosophila can help to tackle this complexity. A nice example has just been published by Frederic Saudou and colleagues in Cell (Zala et al, 2013). They show that ATP produced by mitochondria is dispensable for fast axonal transport. Instead, GAPDH (glyceraldehyde 3-phosphate dehydrogenase) localises on transported vesicles and performs local glycolysis, thus providing ATP as “on-board energy” for the motor proteins. This is an exciting and fundamentally new concept that makes axonal transport over these enormous distances far better understandable. Importantly, fly genes encoding cytoskeletal machinery are well conserved with mammals, implying that Drosophila‘s proven track-record in solving complex biological problems and delivering evolutionary conserved mechanisms and concepts (Bellen et al., 2010) will hold true also in this case.

This notion is nicely illustrated by a beautiful recent study from Casper Hoogenraad and colleagues who demonstrated the fundamental roles of mammalian TRAK1 and 2 (TRAFFICKING PROTEIN, KINESIN-BINDING) in linking mitochondria to motor proteins during microtubule-based axonal and dendritic transport (van Spronsen et al., 2013). The TRAK homologue Milton and its essential roles in mitochondrial transport were first discovered in Drosophila (Stowers et al., 2002).  As expected, matters turn now out to be more complex in mammals. However, the fundamental principles are shared, and this is where the fly can be used as a powerhouse for new ideas and discoveries, inspiring research on higher animals or even human disease.

Andreas Prokop

References:

  1. Zala, D., Hinckelmann, M.-V., Yu, H., Lyra da Cunha, Marcel M., Liot, G., Cordelières, Fabrice P., Marco, S., and Saudou, F. (2013). Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152, 479-491 –LINK
  2. Bellen, H. J., Tong, C., and Tsuda, H. (2010). 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci 11, 514-522 – LINK
  3. van Spronsen, M., Mikhaylova, M., Lipka, J., Schlager, Max A., van den Heuvel, Dave J., Kuijpers, M., Wulf, Phebe S., Keijzer, N., Demmers, J., Kapitein, Lukas C., Jaarsma, D., Gerritsen, Hans C., Akhmanova, A., and Hoogenraad, Casper C. (2013). TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites. Neuron 77, 485-502 –LINK
  4. Stowers, R. S., Megeath, L. J., Gorska-Andrzejak, J., Meinertzhagen, I. A., and Schwarz, T. L. (2002). Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36, 1063-1077 – LINK
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Present and future drugs to interfere with cytoskeletal functions

Disregarding feasibility of use, what types of drugs are in principle available to interfere with cytoskeleton functions?

  1. Compounds that interfere with microtubule or F-actin stability and dynamics: These drugs are important because we know that microtubules and microtubule dynamics and F-actin are essential in axon regeneration and in synaptic function (rearrangement of F-actin and invasion of microtubules into spines in response to synaptic activity). One advantage of these drugs is that they are specific for the cytoskeleton (as opposed to drugs that target posttranslational modification enzymes; see below).
  2. Compounds directed against protein kinases that regulate cytoskeleton-associated proteins: of these, ROCK inhibitors are already being tested for their effect in promoting regeneration. Inhibitors for other kinases (GSK-3, cdk5, JNK1, 2 and 3, etc) are available, but kinase inhibitors in principle have two problems: 1) most of them are not specific for a single kinase and 2) even if they were, they would affect not only the cytoskeleton but also non-cytoskeletal targets of these kinases. However, in keeping with the idea that systemic targeting of the ubiquitous cytoskeleton can be beneficial (example schizophrenia), we might also consider that systemic targeting of a pleiotropic kinase could be an option. An even broader spectrum of effects would be expected from phosphatase inhibitors.
  3. Compounds that target enzymes involved in posttranslational modifications of cytoskeletal components: Good examples are drugs inhibiting acetylation (HDAC inhibitors) or nitrosylation (nNOS). These too will not only affect cytoskeletal proteins, but also other cellular components, which could be considered an advantage or a disadvantage.
  4. Compounds that interfere with second messengers: for example, drugs targeting cAMP, cGMP (phosphodiesterase inhibitors) and calcium (channel blockers) have pleiotropic effects including indirect effects on the cytoskeleton.

To my knowledge we have currently not available: drugs that interfere directly with specific MAPs, actin-associated proteins or motor proteins. To develop strategies to targets these proteins specifically could be one major goal of an extended commitment to neural cytoskeleton research.

Friedrich Propst

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Relevance of nEUROskeleton research for human society

During the last 5 or 6 years fundamental new insights into the role of the neural cytoskeleton have emerged. These findings have completely changed our perception of the cytoskeleton as a potential target for therapeutic intervention in neurological diseases. A short list of the most pertinent findings in my view:

  • We know that mutations in genes encoding neural cytoskeleton components can cause severe developmental problems in the human CNS (for example, mutations in tubulin genes TUBA3 and TUBB3, in the gene for the microtubule-associated protein Tau (MAPT), and in genes encoding the microtubule motor associated regulators doublecortin and Lis1). These mutations lead to mental retardation in humans, underlining the importance of proper function of the neural cytoskeleton.
  • Neural cytoskeleton components are involved in psychiatric disorders (for example, microtubule regulators in schizophrenia).
  • Neural cytoskeleton components are involved in neurodegenerative diseases (for example, the microtubule-associated protein Tau in Alzheimer’s disease).
  • The proper function of the neuronal cytoskeleton is essential for regenerative processes after injury in the peripheral and central nervous system.
  • Finally and perhaps most importantly, therapeutic targeting of neural cytoskeleton components by drugs can have beneficial effects. Probably the most dramatic examples are the positive effects of drug-induced stabilization of microtubules in axon regeneration and in a mouse model of schizophrenia.

In my view these findings more than justify a strong commitment to further research. The initial goals of these activities could be

  • extended efforts to identify links between additional neurodegenerative and psychiatric disorders and the cytoskeleton
  • a deeper understanding of the molecular mechanisms involved, for example, the molecular and cell biological consequences of changes in microtubule and F-actin dynamics, the role of posttranslational modifications of tubulin, actin and associated proteins, and the regulation of the activity of cytoskeletal-associated proteins
  • the development of new drugs to interfere with cytoskeletal functions that are either more suitable for use in humans than existing ones or specifically target cytoskeletal components that have so far eluded intervention such as specific microtubule- or actin-associated proteins or motor proteins.

Friedrich Propst

 

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