SINO is a newly described syndrome characterized by Spastic paraplegia, Intellectual Disability, Nystagmus and Obesity, caused by heterozygous mutations in the KIDINS220 gene. KIDINS220 (kinase D interacting substrate of 220kDa) is a multi-functional scaffold protein abundantly expressed across the nervous system that participates in neural cell survival, maturation and plasticity. In our work, we study the physiopathology of KIDINS220 mutations following three parallel approaches. (i) We examined the molecular effects of KIDINS220 mutations in HEK293T and primary neurons. Immunocytochemistry revealed that truncating mutations form aggregates and colocalise with p62 and calnexin. Investigation of mitochondrial membrane potential revealed adverse effects of the mutant proteins on mitochondrial health. Protein extraction followed by western blot analysis confirmed that mutated proteins aggregates, unlike the WT, and accumulate in the insoluble fraction. We hypothesise that the mechanisms behind aggregate formation represent a potential druggable target for treatment of KIDINS220-related pathologies. (ii) A combination of in silico techniques was used to design a pipeline to establish the targetability potential of disease-causing KIDINS220 missense mutations, understand the altered molecular events downstream of the selected mutations, and ultimately pioneer drug discovery efforts based primarily on drug repurposing. A similar approach was successfully applied to a case of infantile ascending hereditary spastic paraplegia (IAHSP). (iii) In parallel with the experimental work, we teamed with clinicians and patients’ families to prepare the first clinical overview of SINO syndrome, which should become the reference for newly diagnosed patients.This Project is funded by the PNRR Programme (Project n. 20224YX5ZX).