Descrizione del progetto
Svelare l’origine molecolare della neurodegenerazione
L’atrofia muscolare spinale (SMA) e la sclerosi laterale amiotrofica (SLA) sono malattie progressive che colpiscono i motoneuroni, con effetti devastanti sui pazienti. Il progetto Neurovulnerability, finanziato dall’UE, sta studiando il meccanismo a causa del quale la proteina SMN, necessaria per la sopravvivenza dei motoneuroni, ne provoca la degenerazione selettiva. Gli scienziati stanno indagando la possibilità che la carenza della proteina SMN provochi una disfunzione dell’autofagia lisosomiale, che a sua volta causerebbe l’accumulo di aggregati intracellulari e inciderebbe su neuroni specifici. A tal fine, i ricercatori useranno cellule staminali pluripotenti indotte derivate da pazienti per studiare sottotipi neuronali selettivi e impiegheranno la Drosophila per identificare nuovi percorsi molecolari fondamentali per la neuropatologia della proteina SMN. Complessivamente, lo studio svolto nell’ambito del progetto Neurovulnerability ha le potenzialità per svelare nuovi bersagli terapeutici per le malattie dei motoneuroni.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
53127 Bonn
Germania