Scientists at the University of Manchester have uncovered how the
internal mechanisms in nerve cells wire the brain. The findings open up
new avenues in the investigation of neurodegenerative diseases by
analysing the cellular processes underlying these conditions.
Dr Andreas Prokop and his team at the Faculty of Life Sciences have
been studying the growth of axons, the thin cable-like extensions of
nerve cells that wire the brain. If axons don't develop properly this
can lead to birth disorders, mental and physical impairments and the
gradual decay of brain capacity during aging.
Axon growth is directed by the hand shaped growth cone which sits in
the tip of the axon. It is well documented how growth cones perceive
signals from the outside to follow pathways to specific targets, but
very little is known about the internal machinery that dictates their
behaviour.
Dr Prokop has been studying the key driver of growth cone movements,
the cytoskeleton. The cytoskeleton helps to maintain a cell's shape and
is made up of the protein filaments, actin and microtubules.
Microtubules are the key driving force of axon growth whilst actin helps
to regulate the direction the axon grows. Dr Prokop and his team used fruit flies to analyse how actin and
microtubule proteins combine in the cytoskeleton to coordinate axon
growth. They focussed on the multifunctional proteins called
spectraplakins which are essential for axonal growth and have known
roles in neurodegeneration and wound healing of the skin.
What the team demonstrate in this recent paper is that spectraplakins
link microtubules to actin to help them extend in the direction the
axon is growing. If this link is missing then microtubule networks show
disorganised criss-crossed arrangements instead of parallel bundles and
axon growth is hampered. By understanding the molecular detail of these interactions the team
made a second important finding. Spectraplakins collect not only at the
tip of microtubules but also along the shaft, which helps to stabilise
them and ensure they act as a stable structure within the axon. This additional function of spectraplakins relates them to a class of
microtubule-binding proteins including Tau. Tau is an important player
in neurodegenerative diseases, such as Alzheimer's, which is still
little understood. In support of the author's findings, another
publication has just shown that the human spectraplakin, Dystonin,
causes neurodegeneration when affected in its linkage to microtubules.
Talking about his research Dr Prokop said: "Understanding
cytoskeletal machinery at the cell level is a holy grail of current cell
research that will have powerful clinical applications. Thus,
cytoskeleton is crucially involved in virtually all aspects of a cell's
life, including cell shape changes, cell division, cell movement,
contacts and signalling between cells, and dynamic transport events
within cells. Accordingly, the cytoskeleton lies at the root of many
brain disorders. Therefore, deciphering the principles of cytoskeletal
machinery during the fundamental process of axon growth will essentially
help research into the causes of a broad spectrum of diseases.
Spectraplakins like at the heart of this machinery and our research
opens up new avenues for its investigation".
What Dr Prokop's paper in the Journal of Neuroscience also
demonstrates is the successful research technique using the fruit fly Drosophila.
The team was able to replicate its findings regarding axon growth in
mice which in turn means the findings can be translated to humans. Dr Prokop points out fruit flies provide ideal means to make sense of
these findings and essentially help to unravel the many mysteries of
neurodegeneration.
Dr Prokop continues: "Understanding how spectraplakins perform their
cellular functions has important implications for basic as well as
biomedical research. Thus, besides their roles during axon growth,
spectraplakins of mice and humans are clinically important for a number
of conditions and processes including skin blistering,
neuro-degeneration, wound healing, synapse formation and neuron
migration during brain development. Understanding spectraplakins in one
biological process will instruct research on the other clinically
relevant roles of these proteins."
The recently published paper represents six years of work by Dr Prokop and his dedicated team.
Journal Reference:
- Juliana Alves-Silva, Natalia Sánchez-Soriano, Robin Beaven, Melanie Klein, Jill Parkin, Thomas H. Millard, Hugo J. Bellen, Koen J. T. Venken, Christoph Ballestrem, Richard A. Kammerer, and Andreas Prokop. Spectraplakins Promote Microtubule-Mediated Axonal Growth by Functioning As Structural Microtubule-Associated Proteins and EB1-Dependent TIPs (Tip Interacting Proteins). Journal of Neuroscience, July 4, 2012 DOI: 10.1523/%u200BJNEUROSCI.0416-12.2012