Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue

Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway

Hormonal exposures and the risk of intracranial meningioma in women: a population-based case-control study

Professor. Authors Phillips, Koepsell, and Van Belle are also UW professors/researchers.Background: The role of exogenous hormone exposures in the development of meningioma is unclear, but these exposures have been proposed as one hypothesis to explain the over-abundance of such tumors in women. Methods: The association between oral contraception (OC) or hormone replacement therapy (HRT) and intracranial meningioma in women was investigated using a population-based, matched case-control study. Exposures for 143 cases and 286 controls matched on age within five years were obtained by interview. Diagnoses were confirmed histopathologically and estrogen and progesterone receptor assays conducted. Results: Although risk of meningioma appeared modestly elevated in past OC users (OR = 1.5, 95% CI 0.8 - 2.7), and in current users (OR = 2.5, 95% CI 0.5 - 12.6), the confidence intervals were wide. No significant association between meningioma risk and duration of OC use was found. Likewise, risk of meningioma was only weakly associated with past use of HRT (OR = 0.7, 95% CI0.4 - 1.3), and not at all with current use of HRT (OR = 1.0, 95% CI 0.5 - 2.2). Of 142 available specimens, 2 (1%) expressed estrogen receptors, whereas 130 (92%) expressed progesterone receptors (PR). OC use was associated with increased risk of a meningioma expressing less rather than more PR (OR = 3.2, 95% CI 1.3 - 8.0). Overall, in post menopausal women, HRT use appeared to confer a non-significant protective effect, and was not associated with low or high PR expressing meningiomas. Conclusion: This study found little evidence of associations between meningioma and exogenous hormone exposures in women but did suggest that some hormonal exposures may influence tumor biology in those women who develop meningioma.This study was funded by a grant (CA 60710) from the National Cancer Institute, Bethesda, Maryland, USA