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1 Acta Neurobiologiae Experimentalis

1 2009

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How neurons become giant-identification of proteins regulated by mTOR kinase in etiopathology of tuberous sclerosis

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Malik A. , Swiech L. , Perycz M. , Urbanska M. , Blazejczyk M. , Wulf P. , Parobczak K. , Pietruszka P. , Zarebska M. , Rutowicz K. , Jaworski J.

Acta Neurobiologiae Experimentalis

2009

tom 69

nr 3

mTOR is a serine-threonine protein kinase for several aspects of neuronal function. Increased mTOR signaling has been implicated in tuberous sclerosis (TS), a multiorgan disease affecting brain. TS is caused by mutations in genes encoding for hamartin and tuberin that lead to increase of the mTOR activity and subsequent abnormal cell growth and proliferation, leading to brain lesions containing giant cells. It is unclear how mTOR contributes to observed changes. Our aim was to identify downstream mTOR effectors important for the disease related abnormal cell growth. To model TS giant cells, rat cortical neurons cultured in vitro were transfected with short interfering RNA (siRNA) targeting tuberin that caused a Rapamycin-sensitive increase of neuron soma size. Next, we designed a siRNA library directed against 140 mRNAs encoding potential mTOR targets, selected based on published data. To select siRNAs decreasing soma size of enlarged cells, cortical neurons were contransfected with tuberin siRNA together with siRNAs from the library. Our screen revealed over 20 genes, whose expression downregulation reversed the giant-cell like phenotype and 6 siRNAs that further increased size of cells with tuberin knockdown. Among proteins contributing to abnormal neuron growth upon mTOR overactivation, we identifi ed those involved in actin cytoskeleton dynamics, vesicular transport and cellular signaling. This work has been fi nanced by PBZ-MNiI-2/1/2005 and PNRF-96- AI-1/07 grants.