Descripción del proyecto
Desvelar la base molecular de la neurodegeneración
La atrofia muscular espinal (AME) y la esclerosis lateral amiotrófica son enfermedades progresivas de las motoneuronas con unos efectos devastadores en los pacientes. El proyecto Neurovulnerability, financiado con fondos europeos, está investigando el mecanismo por el que la proteína de supervivencia de las motoneuronas (SMN) provoca una degeneración selectiva de las motoneuronas. Los científicos están estudiando la posibilidad de la que deficiencia de SMN lleve a una disfunción de la autofagia lisosómica que resulte en la acumulación de agregados intracelulares y afecte a neuronas específicas. Para ello, utilizarán células madre pluripotentes inducidas derivadas de pacientes para estudiar subtipos neuronales selectivos, y «Drosophila melanogaster» para identificar nuevas rutas moleculares esenciales para la neuropatología de las SMN. En conjunto, el estudio Neurovulnerability podría desvelar nuevas dianas terapéuticas para enfermedades de las motoneuronas.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
53127 Bonn
Alemania