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The Roles of Presenilin and FKBP14 in Drosophila Development and Notch Signalling; Diana L. van de Hoef, Department of Molecular Genetics, University of Toronto, 2008. The multimolecular gamma-secretase complex cleaves type 1 transmembrane proteins such as Notch and one of the genes targeted in Alzheimer’s disease known as APP. This complex comprises four components, known as anterior pharynx defective 1, presenilin enhancer 2, nicastrin and presenilin. Presenilin is an aspartyl protease that comprises the catalytic core of gamma-secretase, and mutated forms of presenilin cause early-onset familial Alzheimer’s disease. To further define the role of Drosophila Presenilin (Psn), I performed a genetic modifier screen to identify Psn-interacting genes. One of the genes that was identified, known as FKBP14, encodes a peptidyl-prolyl isomerase that may be involved in protein folding in the ER. I demonstrate that an immunosuppressant drug known as FK506, which binds FKBPs and abrogates their function, reduced Psn, anterior pharynx defective 1 and presenilin enhancer 2 protein levels in vivo. I also show that FKBP14 colocalized with anterior pharynx defective 1 and Psn in the ER, suggesting a role in gamma-secretase stability. Consistent with this, I demonstrate that FKBP14 binds with Psn and mediates Psn stability and Notch signalling in vivo. To further characterize the role of FKBP14 in development, I analyzed its expression pattern and phenotypes of an FKBP14 null mutant. I show that FKBP14 localized to embryonic hemocytes and larval tissues, in addition to being expressed in developing egg chambers. FKBP14 function is required during development, since FKBP14 null mutants are recessive lethal. These mutants exhibited defects in larval disc development that resulted in eye, wing and notum phenotypes reminiscent of Psn dominant-negative and Notch-dependent phenotypes. Furthermore, FKBP14 mutants displayed enhanced apoptosis in larval tissues, suggesting a possible involvement in apoptosis regulation. I then examined the effects of FKBP14 overexpression, and observed enhanced Psn protein levels in vivo. Interestingly, co-expression of FKBP14 and Psn resulted in synergistic bristle phenotypes, suggesting a role for FKBP14 function in the Notch signalling pathway. Consistent with this, FKBP14 mutants enhanced Notch loss-of-function phenotypes in the wing. Altogether, my data demonstrate an essential role for FKBP14 during development, particularly in Psn protein maintenance and Notch signalling.

This study investigated the symptom of recurrent leg pain of unknown aetiology (PUA) in children and adolescents with 22q11 deletion. A leg pain questionnaire was designed and administered to 300 patients with 22q11 deletion and to 4507 school children. Replies were received from 119 patients (Return rate 39.6%) and from 1391 school children (Return rate 30.8%). A standard battery of clinical tests was applied to 108 patients with 22q11 deletion and mechanical therapy of diagnosed biomechanical foot abnormalities was instituted. The prevalences of PUA, sleep disturbance and exercise intolerance were found to be significantly higher in patients with 22q11 deletion compared with children of the general population. The clinical picture of PUA is reported and the previously unrecorded association between PUA, sleep disturbance and exercise intolerance is demonstrated in patients with 22q11 deletion. The implications of the differences in the clinical picture and the symptom association between the two populations are discussed. The ages of 8-9 years and 12-13 years emerged as periods during which a possible significant change may occur leading to a dramatic change in the prevalence of PUA, sleep disturbance and exercise intolerance. The clinical study reports the prevalence of biomechanical foot abnormalities in children with 22q11 deletion and presents evidence of the efficacy of mechanical therapy in alleviating patient’ symptoms. The association between biomechanical foot abnormalities and PUA, sleep disturbance and exercise intolerance is explored. This work suggests a possible multifactonal aetiology for the symptoms of PUA, sleep disturbance and exercise intolerance in patients with 22q11 deletion and recommends biomechanical assessment and mechanical therapy if appropriate for symptomatic patients