Post-transcriptional regulation in motor and cognitive disorders

Healthy neurons are very long cells, taking local decisions far away from their cell body. They are in this respect different from any other cell of our body. For this reason, they have built mechanisms of local decision-making unique to them. They also need to take different decisions in different parts of their extensions (called axons, dendrites and synapses) and for this, express genes that are able to produce a complex series of proteins. These genes are making one immature messenger RNA that can be cut (splicing) into many different versions, themselves translated into different proteins.

As they are expressing many mature messengers by splicing, the neurons crucially need to control these alternative splicing. Problems in achieving these events are giving severe problems to the neurons. In the past 10 years, human genetic discovered that mutations in genes producing the splicing machinery are causing neurodegenerative disorders.

We recently discovered the essential nuclear and cytoplasmic roles of such splicing factor, called SFPQ in motor circuit development and degeneration and found a novel type of splicing regulation, the cryptic last exon (CLE), normally repressed by SFPQ. This aberrant splicing event, often achieved at the expense of the normal messenger RNAs, produces stable short transcripts able to make interfering proteins, perfect candidates to carry pathologies typical of neurodegenerative processes.

Our initial study showed strong evidence for a key role of SFPQ in Amyotrophic Lateral Sclerosis/Fronto-temporal dementia (ALS/FTD) neurodegenerative processes. In the past months, unambiguous findings show that loss of SFPQ is an early hallmark across sporadic and familial ALS patient iPSC-derived motor neurons in culture, putting this protein at the centre of motor degenerative mechanisms. Our ongoing studies of newly identified "SFPQ patients" indicates that the protein is likely to be at the core of a wider variety of degenerative disorders, including neurodevelopmental syndromes.

We therefore propose to use our unique models to understand how loss, or mutations, of SFPQ protein during neuronal maturation and in adult circuits generates these CLE transcripts and identify the molecular and cellular consequence of CLE short transcripts on developing and adult neurons. These are of direct importance to develop early therapeutic avenues against neurodegeneration, targeting key pathogenic CLEs. In addition, better understand the CLE-generating novel splicing regulation is likely to have implications on a wider set of splicing-dependent pathologies such as cancers.

Genome-wide analyses revealed that defects in control of alternative splicing are most frequently linked with human diseases. We recently uncovered the essential nuclear and cytoplasmic roles of the splicing factor SFPQ in motor circuit development and degeneration and found a novel type of splicing regulation, the cryptic last exon (CLE), normally repressed by SFPQ. This aberrant splicing event, often achieved at the expense of the normal variants, produces stable short transcripts, some of these encoding interfering proteins, perfect candidates to carry pathologies typical of neurodegenerative processes.

Our initial study showed strong evidence for a key role of SFPQ in Amyotrophic Lateral Sclerosis/Fronto-temporal dementia (ALS/FTD) neurodegenerative processes. In the past months, unambiguous findings show that loss of SFPQ is an early hallmark across sporadic and familial ALS patient iPSC-derived motor neurons in culture, putting this protein at the centre of motor degenerative mechanisms. Our ongoing studies of newly identified "SFPQ patients" indicates that the protein is likely to be at the core of a wider variety of degenerative disorders, including neurodevelopmental syndromes.

We therefore propose to use our unique animal models to understand how loss - or mutations - of SFPQ protein during neuronal maturation and in adult circuits, generates these CLE transcripts and identify the molecular and cellular consequence of CLE short transcripts on developing and adult neurons. These are of direct importance to develop early therapeutic avenues against neurodegeneration, targeting key pathogenic CLEs. In addition, better understand the CLE-generating novel splicing regulation is likely to have implications on a wider set of splicing-dependent pathologies such as some cancers.

1. Academic impact
The expected beneficiaries of this research proposal are mainly the scientists and clinicians in the fields of cell biology, developmental neurobiology and neurodegenerative disorders.
2. From basic research to clinic
The beneficiaries are clinicians working on neurodegenerative disorders as this project will lead to identification of novel molecules and molecular mechanisms involved in neurodegenerative processes. We will engage with international clinicians specialized in neurodegenerative pathologies both by participating to clinical symposia and by collaborating extensively on SFPQ pathologies in human,
3. Application and exploitation:
Any commercial potential of our discoveries will be discussed with KCL enterprise. Potential commercial outcome may stem from this proposal but will require further research development before any commercial ventre can be envisaged. However, development of research projects with the industry may well stem from the proposed research.

4. Training benefiting to Industry and Private sector
The two researchers funded by the grant as well as the applicant are training undergraduate, master and postgraduate students who will greatly benefit from what they learn during their training. The skills learned will equip them to their next steps in their professional life. A majority of our undergrad and graduate trainees pursue a career outside of academia, strengthened by the wide variety of skills acquired during their training in our lab.

5. Communications and engagement:
The lead applicant is communicating her results through public lectures in school and public events organised by various organisations. She also teaches at and directs international courses and organises international workshops (eg. EMBO. MBL).
The IoPPN is in the process of developing a website for public communications of research output that will be used by the applicants.

The findings will be shared with the public. All peer-reviewed articles will be published in Open Access format and findings will be explained in the form of public lectures and illustrations/3D model made for public science exhibitions. The lead applicant has contact with the BBC to explore possibilities of a new form of public communication of our results promoting at the same time the impact of basic research on Health and the involvement of women in research advances.

See Pathways to Impact for more info.