Tag Archives: tubulin

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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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

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The remit of this blog

This blog will be a forum for Researchers from Europe and beyond sharing an interest in the role and regulation of the cytoskeleton during brain development, function, regeneration and degeneration, both in health and disease. More will follow explaining the rationale, timeliness, importance and vast opportunities of this kind of research.

Upcoming meetings:

  1. The microtubule cytoskeleton in development and disease, Barcelona, Spain. 18-20 March, 2013; LINK
  2. Growing to Extremes: Cell Biology and Pathology of Axons, Granlibakken Resort, Tahoe City, California, USA, March 10—15, 2013; LINK
  3. Batsheva Workshop on Spatial Challenges in Neuronal Cell Biology, Lopatie Conference Center, Weizmann Institute of Science, 28-29 April 2013; LINK

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