Biology subjects

Fraser, G.

Publications and source records attributed to Fraser, G..

3 recordsLinked to original sources

bioRxiv2025

The Rise and Fall of SARM1 Base-Exchange Inhibitors

The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a new class of base-exchange inhibitors (BEXi) targeting SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.

neuroscience↗

bioRxiv2025

Proteomic Analysis Links Truncated Tau to Lysosome Motility, Autophagy and Endo-lysosomal Dysfunction

Tauopathies are characterized by the progressive accumulation of abnormal tau species, which disrupt the autophagy-lysosomal pathway (ALP), a critical system for degrading intracellular macromolecules and aggregated proteins, causing toxicity and cell death. This study investigates the impact of the N-terminally truncated Tau35 protein overexpression on proteolytic pathways, including effects on autophagy and endo-lysosomal processes. Using a Tau35 mouse model and SH-SY5Y cell lines stably expressing either the Tau35 fragment or full-length tau, we employed western blotting, proteomic analysis of lysosome-enriched brain fractions, proteolysis/endocytosis assays, and live-cell imaging with the lysotracker reporter to assess protein degradation and lysosomal function. Our findings identify early pathological changes in endo-lysosomal processes, including increased endocytosis, proteolytic dysfunction and lysosomal motility abnormalities, associated with Tau35-induced toxicity. This work extends previous research by providing new insights into the mechanisms of Tau35-induced neurotoxicity, offering a foundation for developing targeted therapeutic strategies to address tauopathies.

neuroscience↗

bioRxiv2017

Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways

A current working model is that Alzheimer's disease actively spreads from diseased to healthy neurons, mediated by transfer of extracellular, abnormal, disease-specific forms of the microtubule-associated protein tau. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia, or reflects a constitutive biological process. We report two mechanisms of entry of monomeric tau to neurons: a rapid early dynamin-dependent phase, and a second, slower actin-dependent phase, suggesting that monomeric tau enters neurons via rapid saturable clathrin-mediated endocytosis and also by bulk endocytosis. Aggregated tau entry is independent of actin polymerisation and largely dynamin dependent, consistent with clathrin-mediated endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate tau entry into neurons, with tau carrying antibody with it into neurons, indicating that antibody binding is insufficient to prevent neuronal tau entry.

neuroscience↗