Pretzel syndrome (PS) is a recently described autosomal recessive disorder characterized by abnormal brain development and intractable epilepsy. All affected children harbor a large homozygous deletion in the STRADa gene, which encodes for the pseudokinase STRADa (STE20 Related Adaptor alpha). The underlying pathogenic mechanisms of PS and the role of STRADa in cortical development remain unknown. The only characterized function of STRADa is to bind and activate LKBl, which serves as an upstream activating kinase to AMPK-related kinases, including AMPK and SAD-A/B Kinases. Phosphorylated AMPK inhibits downstream mTOR signaling while phosphorylated SAD-A/B controls neuronal polarization and axonogenesis. In addition, recent reports suggest that LKBl also regulates neuronal migration during corticogenesis. Interestingly, mutations in LKBl give rise to Peutz-Jeghers syndrome (PJS), a distinct autosomal dominant disorder characterized by intestinal polyposis and increased cancer incidence. Phenotypic disparities between PJS and PS suggest that STRADa may have additional LKBI-independent functions. This proposal aims to define the cortical histopathology of PS, determine the function of STRADa during cortical development, and identify novel binding partners of STRADa. The focus of Aim 1 is to determine the histopathological and cell-signaling abnormalities of PS brain tissue. The focus of Aim 2 is to define the in vitro and in vivo role of STRADa during cortical development using shRNA-mediated knockdown of STRADa in developing neurons. The focus of Aim 3 is to identify novel binding partners of STRADa by using co-immunoprecipitation coupled with mass spectrometry analysis. These experiments will provide novel insight into the function of STRADa during cortical development and elucidate the role of STRADa in the pathogenesis of PS. Several devastating neurodevelopmental disorders, such as Tuberous Sclerosis Complex (TSC) and certain types of autism associated with epilepsy, have been shown to result from mutations in genes the protein products of which are regulate the mTOR signaling cascade. Further elucidation of the neurodevelopmental role of STRADa, which may serve to inhibit downstream mTOR signaling, will provide further insight into the mechanisms that modulate mTOR activity during cortical development and may thereby lead to identification of novel therapeutic targets.
| Orlova, Ksenia A; Crino, Peter B (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184:87-105 |
