Project description
Unveiling the molecular basis of neurodegeneration
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are progressive motor neuron diseases with devastating effects on patients. The EU-funded Neurovulnerability project is investigating the mechanism by which the survival of motor neuron (SMN) protein leads to selective motor neuron degeneration. Scientists are exploring the possibility that SMN deficiency leads to a lysosome-autophagy dysfunction that results in the accumulation of intracellular aggregates and impacts specific neurons. For this purpose, they will use patient-derived induced pluripotent stem cells to study selective neuronal subtypes and Drosophila to identify new molecular pathways essential for SMN neuropathology. Collectively, the Neurovulnerability study has the potential to unveil novel therapeutic targets for motor neuron diseases.
Objective
The mechanisms behind neuronal death in different motor neuron diseases (MND) remain unknown. These MNDs include the devastating spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). A fascinating question in neurodegeneration research is why mutations in ubiquitously expressed genes result in the selective death of a specific neuronal subtype. The ubiquitously expressed and conserved survival of motor neuron (SMN) protein receives its name because its deficit results in MN degeneration. However, SMN known functions -spliceosome assembly and axonal mRNA transport- do not explain the selective MN vulnerability.
Accumulation of intracellular aggregates in neurons is a hallmark of most neurodegenerative diseases. The lysosome-autophagy system is the main catabolic pathway for recycling of protein aggregates and damaged organelles, and its role as a quality control system is especially critical in neurons, due to their postmitotic and highly specialized nature. The hypothesis for this proposal is that SMN deficiency leads to a lysosome-autophagy dysfunction which results in a proteostatic failure, underlying MN degeneration. Furthermore, the existing heterogeneity in SMN protein levels across MN populations may determine their probability of survival.
To test these hypotheses we will use the CRISPR/Cas9 system to genetically engineer human control, SMA and ALS patient-derived iPSCs to generate isogenic and reporter lines that will allow us to study selective neuronal subtypes at a single-cell level. We will also follow an interdisciplinary approach using a SMA Drosophila model to identify new molecular pathways essential for SMN neuropathology. Altogether, my research proposal aims at untangling the molecular mechanisms underlying selective MN death. Our results will open up new directions of research into the molecular basis of neurodegeneration and will provide clues for the design of therapeutics targeting specific neuronal types or phases of MNDs.
Fields of science
- natural sciencesbiological sciencesneurobiology
- engineering and technologyenvironmental engineeringwaste managementwaste treatment processesrecycling
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringcontrol systems
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis
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Funding Scheme
ERC-STG - Starting GrantHost institution
53127 Bonn
Germany