Investigating deficits of axonal RNA metabolism and axonal signalling in amyotrophic lateral sclerosis

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Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease (MND), is a devastating neurodegenerative disorder which causes progressive loss of muscle function and paralysis. ALS is incurable and leads to death, usually caused by the inability to breathe, on average only 3 years after diagnosis, with a lifetime risk of about 1 in 400. The main cells affected in this disease are nerve cells called motor neurons (MNs), which progressively die during the course of ALS. MNs are amongst the largest cells of the body and connect the brain and the spinal cord to the muscles therefore making movement possible. In order to do this, MNs rely on one thin process, named the axon, which extends from the spinal cord out to each and every muscle of our body. In adults, a single axon can measure over a meter, running from the spinal cord to our fingers or toes, and needs sophisticated transport and communication systems to survive and function. Importantly, research has shown that abnormalities in axons are found in the very early stages of ALS and other incurable human diseases. All cells in an individual's body, although very diverse from each other, contain the same genetic material called DNA, that gives instructions to each individual cell. Therefore the identity of each cell type (whether a MN or a heart cell, for example) is the result of which portions of DNA are active and produce another type of chemical called RNA. RNA carries all the necessary information for the cell to function. The sum of all the RNA in a cell, named the transcriptome, is the signature that characterises each cell type. Knowing the transcriptome of a certain cell type provides insights into its biology and helps determine the causes of diseases. This is particularly relevant with MNs in ALS since there is good evidence showing that the biological processes linked to RNA 'metabolism' are primarily affected in ALS.Further, RNA is transported in axons and this is essential for axon maintenance and its response to injuries. The findings summarized above, highlighting that: 1) axons are involved in early stages of disease; and 2) ALS is caused by alterations of the RNA repertoire in MNs, alongside with novel preliminary data from my Sponsor's laboratory which shows that 3) key ALS molecules localise to cellular organelles which are involved in the communication system of axons, all converge to form my research questions.I will use a novel animal model of ALS to investigate: a) Which changes occur in the RNA of axons; b) How these changes can play a role in ALS; c) How the communication system between axons and the cell body is affected in ALS. The feasibility of this project is ensured by the recent technological advances provided by my Sponsor's laboratory and collaborators. These cutting edge approaches will allow me to isolate and study RNA specifically found in MNs and their axons. Further, I will be able to isolate the small particles that contribute to transmitting survival signals in MN axons. In summary this project will contribute to understand how axons function normally and what goes wrong in ALS. This will greatly help us to understand disease mechanisms and discover novel targets for effective therapies for ALS.