TELETHON GGP20040 - Elevating spastin by inhibiting its degradation: a possible therapeutic approach in Hereditary Spastic Paraplegia (HSP) (DSB.AD006.321)

Area tematica

Scienze biomediche

Area progettuale

Struttura responsabile del progetto di ricerca

Istituto di biologia e patologia molecolari (IBPM)

Responsabile di progetto

CINZIA RINALDO
Telefono: 0649933879
E-mail: cinzia.rinaldo@uniroma1.it

Abstract

HSP is a 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. A spastin gene dosage-dependent rescue of defects in SPG4-HSP patients' neurons has been reported, providing the proof of principle that corrective spastin elevating approaches are a viable therapeutic strategy.
We found that HIPK2-mediated phosphorylation of spastin at S268 (pS268) promotes its stability by preventing its poly-Ubiquitination (poly-Ub) and neddylation-dependent proteasomal degradation. We showed that targeting the HIPK2/spastin axis represents a strategy to elevate spastin. In particular, we identified MNL4924 as a promising drug to be further validated in patient-derived neurons and in heterozygous SPG4-HSP animal models.
Thus, we plan 1) to dissect the spastin degradation pathway by identifying the molecular players and exploring the contribution of neddylation and pS268; 2) to functionally validate the pharmacological inhibition of neddylation induced by MNL4924 as a therapeutic approach in vivo, and 3) to investigate effects of pS268 on spastin structure/function.

Obiettivi

This proposal is a follow-up to our studies, supported by Italian Telethon Foundation in which we have demonstrated that pS268 stabilizes spastin by preventing its poly-Ub/degradation. We showed a rescue of neurite defects by modulating the HIPK2/spastin axis to restore spastin levels in SPG4-HSP backgrounds. We found that MLN4924, a drug that blocks neddylation, is able to elevate spastin levels in primary neurons mimicking human HSP and in patient-derived cells. Thus, we have now the following objectives:
1. identify the factors involved in spastin poly-Ub, explore their interplay with pS268 and neddylation, and analyze the UPS response of different pathogenetic spastin variants
2. verify that spastin restoration by MNL4924 rescues neurite defects in human SPG4-HSP neurons
3. confirm MNL4924 efficacy to restore spastin levels in mouse and Drosophila in vivo models and verify if inhibition of neddylation improves motor performance in spastin-deficient flies
4. unveil the mechanism through which pS268 affects spastin assembly/activity.

Data inizio attività

02/05/2021

Parole chiave

spastin, Hereditary Spastic Paraplegia (HSP), degradation

Ultimo aggiornamento: 24/08/2025