Hereditary spastic paraplegias (HSP) are inherited rare disorders mainly affecting the corticospinal neurons in pure and complex forms. Over 80 genes are currently associated with HSPs. In complex forms, the disease often overlap with cerebellar ataxia, peripheral neuropathy, optic atrophy, and cerebral palsy (CP). Mutations in HPDL, the gene encoding the T-dark protein 4-hydroxyphenylpyruvate dioxygenase-like, have been associated with a combination of neurodevelopmental disorder with progressive spasticity, epilepsy, brain atrophy, and white matter abnormalities. In vivo studies related to HPDL disease show several limitations related to early lethality in mice and transient effects in zebrafish, while non-neural systems as commonly used cellular lines cannot suffice to explore HPDL-related conditions. Recent investigations suggest that in multicellular eukaryotes HPDL is involved in the synthesis of 4-hydroxybenzoate, the precursor of the quinone ring of Coenzyme Q10 (CoQ10). The central hypotheses of this project are that HPDL is involved in brain development, its ablation leads to a spectrum of disorders wider than those already known, and that alterations of CoQ10 biosynthetic pathways are involved in these processes. Hence, our objectives aim to employ in vitro and in vivo systems to study HDPL in neural development, to shed new light on the CoQ10-HPDL liaison, and to attempt rescuing HPDL phenotype in our models through compounds with an active role in the CoQ10 biosynthetic pathway. To do this, we will use cellular models as HPDL KO neural cell lines, iPSC-derived cortical neurons, and 3D cerebral organoids. iPSCs will be derived from somatic cells taken from newly identified patients. HPDL null zebrafish and knock-in nematode models will be also used for in vivo experiments and to test novel pharmacological approaches. Our final goal will be to translate our findings in the clinic, in a bench-to-bedside perspective.

STUDIO DI MODELLI MULTIPLI DI UNA NUOVA FORMA DI PARAPLEGIA SPASTICA, SPG83 Le paraplegie spastiche ereditarie (HSP) sono disturbi rari ereditati che colpiscono principalmente i neuroni corticospinali. Oltre 80 geni sono noti e la malattia si sovrappone spesso ad atassia cerebellare, neuropatia periferica, atrofia ottica e paralisi cerebrale. Mutazioni in HPDL, il gene che codifica la proteina 4-idrossifenilpiruvato diossigenasi-like, sono state associate a una combinazione di disturbi del neurosviluppo che ricordano la paralisi cerebrale infantile e le malattie mitocondriali (SPG83). Recenti studi suggeriscono che HPDL è coinvolto nella sintesi Coenzima Q10 (CoQ10). Le ipotesi centrali di questo progetto multicentrico sono che HPDL sia coinvolto nello sviluppo del cervello, che la sua perdita porti a uno spettro di disturbi clinici più ampio di quelli già noti e che le alterazioni delle vie biosintetiche del CoQ10 siano coinvolte in questi processi. I nostri obiettivi sono quindi quelli di utilizzare sistemi di laboratorio in vitro (cellule, neuroni derivati da fibroblasti cutanei, organoidi) ed in vivo (modelli knock-out in zebrafish e knock-in nel nematode) per studiare meglio il legame CoQ10-HPDL e tentare di testare nuovi approcci farmacologici. L'obiettivo finale sarà tradurre i nostri risultati in clinica, al letto del paziente.

n/a

SPASTIC PARAPLEGIA TYPE 83

Paraparesi Spastica Familiare