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Assessmet of TBCK deficiency, responsible for the neurodegenerative syndrome IHPRF3, on the neuroglutamatergic differentiation pathway

Grant number: 21/01788-7
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2021
Effective date (End): December 31, 2021
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Maria Rita dos Santos e Passos Bueno
Grantee:Igor Cabreira Ramos
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


TBCK (TBC1 domain-containing kinase) is responsible for coding a kinase protein allegedly associated with vesicle transport (autophagic-lysosome pathway), cellular growth, actin cytoskeleton organization, mTOR pathway transcriptional regulation, tumorigenesis and tumor suppression. TBCK mutations resulting in truncated protein or affecting TBC1 domain are associated with disorders as Infantile Hypotonia with Psychomotor Retardation And Characteristic Facies 3 (IHPRF3). Published data on TBCK suggest a putative GAP (GTPase-Activating Protein) activity for Rab family proteins, associated with vesicle transport. Rab proteins are members of the Ras protein superfamily, which also contains Ran protein - responsible for nuclear-cytoplasmic shuttling. Thus, we hypothesised that TBCK, more specifically TBC1 domain, could also act as GAP for Ran protein. In line with this hypothesis, previous results from our group showed that TBCK-deficient neural cells had diminished expression of TBR1 and TBR2, importante transcription factors for the cortical neurodifferentiation pathway, whereas PAX6, master regulator of this pathway, was overexpressed. Therefore, we suppose that TBCK deficiency may be associated with altered nuclear-cytoplasmic shuttling of transcription factors, particularly those important for the neuroglutamatergic differentiation pathway. In order to confirm this hypothesis, we will assess cytoplasmic and nuclear PAX6 levels in TBCK-deficient and control neural cells derived from induced pluripotent cells (iPSC). As of these results, we expect to better understand TBCK's function and to contribute with the elucidation of the underlying molecular mechanisms of disorders like IHPRF3.

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