Abstract
Finding treatments for rare genetic disorders can be long and frustrating experience. Completion of the Human Genome Project together with advances in next-generation sequencing technologies have extensively contributed to high accuracy and throughput in the diagnosis of genetic disorders. However, due to the limited clinical characterization of patients, the uncertainty of the nature of genetic variants, and lack of mechanistic understanding of disease mechanisms, it is still challenging to achieve precision diagnosis and intervention for rare diseases. This dissertation takes advantages of the genetically amenable model organism, Drosophila, to identify novel variants that cause neurological phenotypes in undiagnosed patients and characterize the underlying neuropathogenesis in vivo. The dissertation starts from the collaborative work with the NIH Undiagnosed Diseases Program (NIH-UDP), in which 16 genes identified from undiagnosed patients are screened through (1) phenotypic characterization of flies with loss-of-Drosophila orthologues; and (2) rescue analysis and causality evaluation. Four genes including SRPK3, NID2, RNASEH2B, and SMS are described in this dissertation. Deleterious mutations in NID2 were found to cause a new disease. The second part of the dissertation focuses on the mechanistic studies of Snyder-Robinson syndrome (SRS). SRS is a rare form of intellectual disability syndrome caused by loss-of-function mutations in spermine synthesis (SMS). However, little is known about the neuropathogenesis. SMS is a polyamine biosynthetic enzyme that converts spermidine to spermine. Polyamines are tightly regulated polycations essential for life. In this dissertation, I show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. SMS deficiency leads to excessive spermidine catabolism, which generates toxic metabolites that cause lysosomal defects and oxidative stress. Consequently, autophagy-lysosome flux and mitochondrial function are compromised in the Drosophila nervous system and SRS patient cells. Importantly, oxidative stress caused by loss of SMS is suppressed by genetically or pharmacologically enhanced antioxidant activity. These findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders.