Biology subjects

Tharp, M. E.

Publications and source records attributed to Tharp, M. E..

4 recordsLinked to original sources

bioRxiv2026

α-Synuclein Seeding in Dopaminergic Neurons Transplanted into the Putamen of Parkinson's Disease Patients

Healthy embryonic neurons grafted into the putamen of Parkinson's disease (PD) patients start to develop Lewy pathology 10 years after transplantation. It remains unclear whether this pathology is initiated by the spread of host-derived -synuclein (syn) aggregates which seed aggregation in the grafted cells or arises independently from a hostile PD environment (e.g., chronic inflammation). To distinguish these possibilities, we identified syn seeding sites in the human brain using a multiplex in situ seed immunodetection (isSID) assay. In PD and dementia with Lewy bodies (DLB), isSID labeled a subset of Lewy pathology (LP) as puncta along neurites and within inclusions. In multiple system atrophy (MSA), isSID labeled Papp-Lantos bodies and microglia. In progressive supranuclear palsy (PSP), isSID labeled tufted astrocytes. isSID labeled neuromelanin in the substantia nigra independent of diagnosis. In 16- and 27-year intraputamenal neuronal grafts, isSID labeled within and proximal to Lewy pathology, as well as outside the grafted tissue. Younger grafts (18 months and 4 years) lacked Lewy pathology. In the 18-month graft, isSID labeled grafted neurons; at 4 years, isSID was confined to amorphous deposits in the graft and was absent from tyrosine hydroxylase-positive grafted neurons. In conclusion, syn seeding is detectable in grafted neurons before and during LP formation. Because seeding accompanies melanization, but is not explained by melanization alone, these findings support host-derived seeds as a contributor to graft pathology.

neuroscience↗

bioRxiv2024

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Whether an individual is a biological female or male affects cancer risk, but the responsible mechanisms and cell types remain obscure. Glioblastoma multiforme (GBM) is a male-biased cancer that is highly aggressive, and resistant to treatment, with poor patient survival. Dismal prognoses in GBM are due in part to the specialized immune system of the brain, consisting largely of microglia, which regulate GBM development and progression. We hypothesized that microglia function differently in females and males and thereby contribute to the observed male bias in GBM. We sorted TAM-MGs (tumor-associated macrophages - microglia) from human GBMs and low-grade gliomas and performed bulk transcriptomic and epigenomic assays to identify sex-biased gene expression. We used published single-cell transcriptomic data from human GBMs to predict sex-biased TAM-MG interactions with other cell types. We found that female and male TAM-MGs mount different inflammatory responses, with female TAM-MGs displaying stronger interferon signaling and cytotoxic T-cell interactions that should enhance anti-tumor immunity in GBM. We validated these sex-differential inflammatory responses experimentally, and determined that genes on the sex chromosomes, specifically those expressed by Xi (the "inactive" X chromosome), drive these differences. Together, our results suggest that sex-differential TAM-MG inflammatory responses contribute to the higher incidence and mortality of GBM in males.

genomics↗

bioRxiv2020

Tumor susceptibility gene-101 regulates glucocorticoid receptor through disorder-mediated allostery

Tumor Susceptibility Gene-101 (TSG101) is involved in endosomal maturation and has been implicated in the transcriptional regulation of several steroid hormone receptors (SHRs), although a detailed characterization of such regulation has yet to be conducted. Here we directly measure binding of TSG101 to one SHR, glucocorticoid receptor (GR). Using biophysical and cellular assays, we show that the coiled-coil domain of TSG101; 1) binds and folds the disordered N-terminal domain (NTD) of GR, 2) upon binding, improves DNA-binding of GR in vitro, and 3) enhances the transcriptional activity of GR in vivo. Our findings suggest that TSG101 is a bona fide transcriptional co-regulator of GR.

biophysics↗

bioRxiv2019

Evading non-essential fetal oocyte attrition maximizes the ovarian reserve

Female reproductive success depends on the size and quality of a finite ovarian reserve. Paradoxically, mammals such as mice and humans eliminate up to 80% of the initial oocyte pool during development through the enigmatic process of fetal oocyte attrition (FOA). Here we report that the combined inhibition of retrotransposon L1 reverse transcriptase and the Chk2-dependent DNA damage checkpoint prevents FOA, thus preserving the entire fetal oocyte population. Remarkably, reverse transcriptase inhibitor AZT-treated Chk2 mutant oocytes initially accumulate, but subsequently resolve L1-instigated genotoxic threats and differentiate, resulting in a maximized functional ovarian reserve. We conclude that FOA is a consequence of genotoxic stress that acts to preserve oocyte genome integrity, and is not an obligatory developmental program for oogenesis.

developmental biology↗