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Tau misfolding into β-sheet–rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer’s disease (AD) pathogenesis. While cryo-EM has resolved the conformation of the AD tau core, the structural features conferring biological activity remain unclear. Here, we investigated how tau filament core structure and post-translational modifications influence seeding capacity in neurons and mice. Our findings show that although filament structure impacts seeding, the AD tau core alone is insufficient to fully replicate AD tau’s biological activity. The unstructured fuzzy coat, particularly phosphorylation within this region, is essential for full seeding competence. Importantly, recombinant tau filaments bearing twelve phospho-mimetic residues (PAD12 tau) and adopting the AD fold recapitulate the seeding activity of native AD tau. These results demonstrate that tau filament pathogenicity arises from the combined contributions of both the ordered core structure and post-translational modifications within the fuzzy coat, providing critical insights into mechanisms underlying tau-driven neurodegeneration. Tau misfolds in Alzheimer’s disease, but how the link between tau filament structure and pathogenicity is unclear. This study shows that both filament core structure and phosphorylation in the fuzzy coat are required for full seeding capacity.

Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism. Metabolite extraction with organic solvents is assumed to remove/denature proteins. Here, the authors uncover a vast landscape of >1,000 proteins in metabolite extracts. These proteins can retain catalytic activity and drive post-extraction metabolite changes, obscuring biological interpretation.

A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson’s disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin ( p  < 0.0001) and higher nigral iron content (SNc: p  < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) =  − 0.501, p  < 0.001). This correlation was significant even in patients newly diagnosed (< 1 year) and stronger in the SNc than any other region examined. This study reveals an early, linear association between low serotonin and higher nigral iron in PD patients, which is absent in controls. This is consistent with a serotonin-iron relationship in the disease process, warranting further studies to determine its cause and directionality.

Markers of chronic infection Toxoplasma gondii (Nicolle et Manceaux, 1908) have been associated with suicidal self-directed violence (SSDV). We present the results of the first study relating T. gondii IgG serology with suicide attempts and suicidal ideation in United States Veterans, known to have higher suicide rates than members of the general population. We also related T. gondii serology to SSDV risk factors, including valid and reliable measures of trait impulsivity, aggression, self-reported depression, and sleep disturbance. We recruited 407 Veterans enrolled at three Veterans Affairs Medical Centers with mean (S.D.) age = 45.6 (11.6) years; 304 men (74.7%); 203 with a history of SSDV and 204 with no history of any self-directed violence (SDV). Seropositivity and serointensity, categorised as high (top quartile) or low (lower three quartiles), were analysed in relationship to SSDV, suicidal ideation and clinical risk factors using age and gender-adjusted linear and logistic methods, after transformations and nonparametric tests when appropriate. Associations between seropositivity and SSDV and its risk factors were not significant in all groups. High serointensity, while not associated with SSDV or repeat suicide attempts, was positively associated with suicidal ideation, depression, impulsivity, and daytime dysfunction due to sleepiness (p < 0.05), but only in Veterans with a history of SSDV. In Veterans without a history of SDV, no associations were significant. These associations remained significant after adjustment for certain socioeconomic factors (i.e., income, homelessness, military rank). Including education in the model downgraded the statistical significance of suicidal ideation and depression to statistical trends, but the significance of associations with impulsivity and daytime dysfunction due to sleepiness remained. Major limitations include the cross-sectional design, overall low seropositivity within the sample, and potentially spurious results due to multiple comparisons. Thus, the results of this report need to be replicated in larger samples, ideally longitudinally.

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles 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 . Using C-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 . Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8 T cell responses .

Metabolomics, a foundational tool in metabolism research, relies on the accurate transmittal of biochemical profiles underlying biological phenotypes. Over the years, workflows used in metabolomics have been assumed to remove enzymes to preserve metabolite levels during processing. Here, we uncover a diverse landscape of over 1,000 proteins, strongly enriched for metabolic enzymes, within metabolite extracts generated using common extraction workflows. Moreover, by combining in-extract stable isotope additions and enzyme inhibitors, we demonstrate transaminase activity, which is preventable by protein removal by 3 kDa filtration. We extend these findings to untargeted metabolomics, revealing that both post-extraction formation of glutamate dipeptide and depletion of total glutathione can also be prevented by removing proteins. Finally, we present a simple yet novel workflow that integrates passive filtration for protein removal of crude metabolite extracts as a superior method for broad-coverage metabolomics. Our findings have broad-reaching experimental implications across all fields that use metabolomics and molecular metabolism, especially cancer, immunology, and diabetes research.Competing Interest StatementThe authors have declared no competing interest.

SARS-CoV-2 corona virus causes a multi-faceted and poorly defined clinical and pathological phenotype involving hyperinflammation, cytokine release. And long-term cognitive deficits, with an undefined neuropathological mechanism. Inflammation increases the activity of the kynurenine pathway, which is linked to neurodegenerative and psychiatric disorders. We sought to determine whether the kynurenine pathway is impacted in patients with mild COVID-19, leading to elevated neurotoxic metabolites in blood, and whether such changes are associated with pro-inflammatory cytokines. Serum samples were taken from 150 patients and analyzed by ELISA and ultra-high performance liquid chromatography (UHPLC). The data were analyzed using multiple linear regression models adjusted for age and sex. We found increased levels of kynurenine, quinolinic acid and 3-hydroxykynurenine in serum from patients with mild COVID-19, together with increased levels of IL-6, ICAM-1, VCAM-1 and neopterin. The levels of neurotoxic metabolites were significantly associated with key inflammatory cytokines including IL-6 and TNFα. The COVID-19 risk-factor hypertension was associated with the highest levels of neurotoxic metabolites in plasma. These neuroactive metabolites could be part of the pathological mechanisms underlying cognitive impairment during and post-COVID and should be explored as potential biomarkers for long-COVID symptoms. Competing Interest Statement P.B. has received support as a consultant from Calico Life Sciences, CureSen, Enterin Inc, Idorsia Pharmaceuticals, Lundbeck A/S, AbbVie, Fujifilm-Cellular Dynamics International, and Axial Therapeutics. He has received commercial support for research from Lundbeck A/S and F. Hoffman-La Roche. He has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc and RYNE Biotechnology. During the time that this paper was written he became an employee of F. Hoffman-La Roche, although none of the data were generated by this company. Footnotes * The affiliations for Matthew Sims, the analysis section on material and methods, as well as a sentence in the abstract have been updated and corrected