Biology subjects

Sundberg, M.

Publications and source records attributed to Sundberg, M..

3 recordsLinked to original sources

bioRxiv2022

Non-Canonical Functions of a Mutant TSC2 Protein in Mitotic Division

Tuberous Sclerosis Complex (TSC) is a debilitating neurodevelopmental disorder characterized by a variety of clinical manifestations including epilepsy, autism, and intellectual disability. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with mTORC1 inhibition, suggesting that multipolar division is an mTORC1-independent phenotype. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC. HighlightsO_LINovel multipolar division in patient-derived iPSCs with mutant form of tuberin, TSC2 encoded protein C_LIO_LIMutant tuberin may act in a dominant negative, mTORC1-independent manner C_LI eTOCTuberous sclerosis complex (TSC) is a disorder caused by mutations in TSC1 or TSC2 genes leading to mTORC1 hyperactivity. Chalkley and colleagues found that a mutant microdeletion allele of TSC2 causes multipolar division in human induced pluripotent stem cells. Chalkley and colleagues also found that the multipolar division from mutant TSC2 may have a dominant negative mechanism and be mTOR1-independent.

cell biology↗

bioRxiv2021

A Tissue-Bioengineering Strategy for Modeling Rare Human Kidney Diseases In Vivo

The lack of animal models for certain human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here we generated kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs to recapitulate a rare kidney tumor called angiomylipoma (AML). Organoids derived from TSC2-/- hiPSCs but not from isogenic TSC2+/- or TSC2+/+ hiPSCs shared a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and developed epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be robustly and consistently recapitulated with transgenic mice. Transplantation of multiple TSC2-/- kidney organoids into the kidneys of immunodeficient rats allowed us to recapitulate AML and cystic kidney disease in vivo, in a scalable fashion and with fidelity, and to test the efficiency of rapamycin-loaded nanoparticles as a novel approach to ablate AMLs by inducing apoptosis triggered by mTOR-inhibition. Collectively, these methods represent a novel tissue-bioengineering strategy for rare disease modeling in vivo.

bioengineering↗

bioRxiv2021

Loss of Tsc1 in cerebellar Purkinje cells induces transcriptional and translation changes in FMRP target transcripts

Tuberous sclerosis complex (TSC) is a genetic disorder that is associated with multiple neurological manifestations. Previously, we demonstrated that Tsc1 loss in cerebellar Purkinje cells (PCs) can cause altered social behavior in mice. Here, we performed detailed transcriptional and translational analyses of Tsc1-deficient PCs to understand the molecular alterations in these cells. We found that target transcripts of the Fragile X Mental Retardation Protein (FMRP) are reduced in mutant PCs with evidence of increased degradation. Surprisingly, we observed unchanged ribosomal binding for many of these genes using Translating Ribosome Affinity Purification (TRAP). Finally, we found that the FMRP target, SHANK2, was reduced in PC synapses, suggesting that compensatory increases in ribosomal binding efficiency may be unable to overcome reduced transcript levels. These data further implicate dysfunction of FMRP and its targets in TSC and suggest that treatments aimed at restoring the function of these pathways may be beneficial.

neuroscience↗