Tag Archives: microtubules

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
Advertisements

Leave a comment

Filed under comment

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

 

Leave a comment

Filed under comment

Thoughts on last year’s nEUROskeleton meeting

I really enjoyed the nEUROskeleton meeting in Brussels last year. What I found most interesting was the emerging realisation that the neuronal cytoskeleton with its “systemic” properties is a prime target for therapeutic intervention not only in regeneration and in preventing degeneration, but even in psychiatric disorders. As was pointed out at the meeting this is, for example, illustrated by the fact that most if not all genes involved in schizophrenia are regulators of microtubules, or by the finding that microtubule stabilising drugs can alleviate schizophrenia-like syndromes in mice lacking a microtubule stabilising protein. To me this made a lot of sense. Changes in nervous system performance cannot be attributed to properties of individual synapses or neurons. The system is dynamic and flexible and huge (in the order of 1014 synapses). To modulate its function it might very well be necessary to slightly modify thousands of neurons and synapses at the same time by targeting components common to all neurons such as the cytoskeleton.

On the other hand, interfering with something as universal as the cytoskeleton appears to be a rather broad and indiscriminative approach. In addition, I think at this point we don’t yet understand what exactly we are doing when we change, for example, microtubule stability. If I am not mistaken, more selective interventions aimed at subgroups of CNS neurons and targeting, for example, mechanisms of interneuronal communication have been shown to be successful in the past.

Nevertheless, I think that the renewed focus in the neuronal cytoskeleton with its “systemic” properties is a fresh and innovative way to look at the CNS. This will definitely open new avenues towards our understanding how the CNS works in health and disease and will lead to new strategies of therapeutic interventions. As indicated above, there is already compelling evidence that this holds great potential.

Friedrich Propst

1 Comment

Filed under comment