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- Speaker: Cinzia Rinaldo
- Title: Spastin elevating approaches to counteract Hereditary Spastic Paraplegia (HSP)
- Researcher Host: Fabiola Moretti
Abstract:
HSP is a motorneuron disease with no effective treatment. Heterozygous loss of function mutations of the SPG4 gene, encoding the microtubule severing AAA+ ATPase spastin, are the most common HSP cause. To date, there is no effective therapy, but recent observations indicate that spastin-recovery approaches are a viable therapeutic strategy.
We found that the kinase HIPK2 phosphorylates spastin at S268 promoting its stability by preventing its neddylation-dependent poly-Ubiquitination (poly-Ub) and proteasomal degradation. We showed that targeting the spastin poly-Ub/degradation pathway represents a strategy to recovery spastin levels in different SPG4-HSP backgrounds. Specifically, we identified an actionable pathway regulating spastin stability and we demonstrated that it is possible to recovery spastin levels and rescue neurite defects by using the neddylation inhibitor MLN4924. Next, we found that the mechanism by which MLN4924 promotes spastin recovery is through inhibition of the DDB1-Cullin-4-Ring-ubiquitin Ligase complex (CRL4). In parallel, we used GAL4/UAS system to generate opportune tissue-specific spastin-deficient Drosophila melanogaster as models to functionally validate our approaches in vivo. Notably, we showed that silencing the expression of Cullin 4 is able to rescue synaptic structure/function and locomotor defects in these spastin-deficient Drosophila melanogaster models. These findings open the way to inhibit spastin degradation by pharmacologically acting at different levels: 1) using MLN4924, a CNS penetrant drug, which is currently in several 2-3 clinical trials; 2) exploiting inhibitors of the CRL4 core complex; 3) developing approaches to specifically inhibit the spastin recruitment at the CRL4.
In parallel, we have developed a imaging-based approach in non-neuronal cells that can be an innovative prognostic and predictive tool in SPG4-HSP, opening up the potential to obtain, non-invasive, biomarkers for SPG4-HSP patients and to set up experimental systems to predict the effectiveness of spastin recovery treatments.
