PhD defence S.N.N. (Saif) Haify

Fragile X-associated Tremor and Ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorders caused by a 55-200 CGG-repeat expansion in the 5’UTR region of the Fragile X Mental Retardation 1 (FMR1) gene. FXTAS patients are clinically characterized by intention tremors and cerebellar gait ataxia. At the molecular levels FXTAS patients have 2- to 8-fold elevated FMR1 mRNA levels and slightly reduced levels of the Fragile X Mental Retardation protein (FMRP). The formation of ubiquitin-positive intranuclear inclusions in neurons and astrocytes is the neuropathological hallmark for FXTAS. Two disease mechanisms, RNA gain-of-function and protein fain-of-function, are hypothesized to be the leading cause of FXTAS. This manuscript mainly focused on the role of the protein gain-of-function disease mechanism, repeat-associated non-AUG (RAN) translation and FMRpolyG. The general aim of this manuscript is to advance our knowledge of FXTAS pathogenesis and neuropathology caused by the expression of FMRpolyG and its accumulation in intranuclear inclusions using a new relevant neuronal cell model and new FXTAS mouse models. We developed a new sandwich-ELISA to quantify soluble and insoluble FMRpolyG protein fractions in post-mortem FXTAS brain tissue. This will hopefully allow for more accurate measurements of FMRpolyG levels and potentially may aid in the search for reliable biomarkers for FXTAS. In addition, a new small molecule therapeutic intervention is proposed in this thesis that is capable of reducing FMRpolyG levels in vitro and in vivo. The results described in this thesis will aid the search for potential biomarkers and the future development of effective targeted therapeutic interventions for FXTAS.

Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.