Biology subjects

Gallik, K. L.

Publications and source records attributed to Gallik, K. L..

4 recordsLinked to original sources

bioRxiv2024

Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability

-Synuclein misfolding and progressive accumulation drive a pathogenic process in Parkinson's disease, yet many brain regions develop more or less pathology than would be predicted by connectivity alone, indicating that intrinsic biological factors influence regional vulnerability. Here, we combined whole brain mapping of -synuclein pathology in wildtype mice 3 days to 9 months after seeding with network diffusion modeling based on anatomical connectivity to derive quantitative measures of regional vulnerability. To identify molecular drivers of this vulnerability, we generated a brain-wide sPAtial Neuron Gene Expression Atlas (PANGEA) and compared regional transcriptional profiles with model-derived vulnerability scores. Vulnerable regions were enriched for specific cellular programs. Specific kinases were also enriched in vulnerable regions, leading to the identification of group II p21-activated kinases (PAKs) as candidate regulators of -synucleinopathy. Pharmacological inhibition of group II PAKs reduced -synuclein aggregation and protected against neuron loss in primary neurons, remained effective when administered after pathology initiation, and suppressed pathology in vivo. Consistent with these findings, genetic depletion of PAK5/6 also suppressed -synuclein aggregation. Together, these results establish a framework linking network-level measures to cellular mechanisms of selective vulnerability and nominate group II PAKs as promising disease-modifying therapeutic targets for Parkinson's disease.

neuroscience↗

bioRxiv2024

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose--independent of energy production--required for CD8+ T cell responses in vivo.

immunology↗

bioRxiv2023

Nf1 Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation

BACKGROUNDNeurofibromin, coded by the NF1 tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1) - a tumor predisposition syndrome caused by a germline NF1 mutation - have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. METHODSTo accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer. RESULTSWe identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance. CONCLUSIONCollectively, these studies uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/539442v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@d4aeeforg.highwire.dtl.DTLVardef@128d9a5org.highwire.dtl.DTLVardef@e8f9e0org.highwire.dtl.DTLVardef@16d0164_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Addition of insoluble fiber to isolation media allows for increased metabolite diversity of lab-cultivable microbes derived from zebrafish gut samples

There is a gap in measured microbial diversity when comparing genomic sequencing techniques versus cultivation from environmental samples in a laboratory setting. Standardized methods in artificial environments may not recapitulate the environmental conditions that native microbes require for optimal growth. For example, the intestinal tract houses microbes at various pH values as well as minimal oxygen and light environments. These microbes are also exposed to an atypical source of carbon: dietary fiber compacted in fecal matter. To investigate how the addition of insoluble fiber to isolation media could affect the cultivation of microbes from zebrafish intestines, an isolate library was built and analyzed using the bioinformatics pipeline IDBac. The addition of fiber led to an increase in bacterial growth and encouraged the growth of species from several phyla. Furthermore, fiber addition altered the metabolism of the cultivated gut-derived microbes and induced the production of unique metabolites that were not produced when microbes were otherwise grown on standard isolation media. Addition of this inexpensive carbon source to media supported the cultivation of a diverse community whose specialized metabolite production may more closely replicate their metabolite production in vivo.

microbiology↗