Unravelling the role of interneurons in Amyotrophic Lateral Sclerosis

In ALS, motoneuron degeneration leads to muscle paralysis. Motoneurons are the final output of the brain since they directly connect to muscles, but their synchronized activation depends on networks of spinal interneurons. We recently showed that in the ALS mice, a subpopulation of inhibitory interneurons is affected early in disease. Inhibitory interneurons lose their synapses on motoneurons, and degenerate. This event can contribute to unbalanced excitability in motoneurons. Our data shows that stabilization of synapses between interneurons and motoneurons by over-expression of a presynaptic organizer, leads to increase motoneuron survival and amelioration of symptoms. However, to date, an approach to selectively target neuronal subpopulations by gene therapy in humans does not exist. Neither it is known if neuronal markers used to identify interneurons in the mouse spinal cord are expressed in human tissue. Thus, we will 1) validate molecular markers for spinal interneurons in human post-mortem tissue by spatial transcriptomics; 2) investigate the fate of interneurons in ALS post-mortem tissue; 3) produce new AAV-PHP.eB viruses carrying neuron-specific enhancers. The overall aim of this project is to generate novel tools for gene therapy. This will allow for non-invasive neurons-specific viral delivery, while decreasing off-target effects. These experiments could bring a novel therapeutic strategy to the field.

We are seeking students with a suitable first degree in molecular biology, neuroscience, medicine, biochemistry or a related discipline, ideally with the following desirable skills and experience:

Background in neuroscience

Genuine interest in neurodegenerative diseases, transcriptomics and gene therapy

Previous training in molecular biology techniques (qPCR, cell culture) and microscopy

Experience in tissue handling for mRNA and protein analysis

Previous experience in bioinformatics and knowledge of R/Python will be considered a plus

Fluent in English (written and spoken)

Ability to perform experiments and to interpret results

Strong background in ALS or other neurodegenerative disorders will be considered a plus

Willingness to learn new techniques

Well-organized, self-motivated, result-oriented and capable of working independently in a collaborative setting