Biology subjects

Warner, T.

Publications and source records attributed to Warner, T..

5 recordsLinked to original sources

bioRxiv2026

Dimerisation and twist reversal of the Lewy fold in α-synuclein mutants with Parkinson's disease and dementia

Dominantly inherited missense and gene dosage mutations in SNCA, the -synuclein gene, cause familial forms of Parkinsons disease and dementia. Here we report the structures of -synuclein filaments from the brains of such individuals. Pathogenic mutations A53T and G51D in SNCA give rise to singlets and doublets of the Lewy fold with a left-handed helical twist in the absence of a peptide-like density for island A. By contrast, filaments from the non-pathogenic variant H50Q consist of singlets of the right-handed Lewy fold with a density for island A, like filaments of wild-type -synuclein. The structures of filaments from homozygous mice transgenic for human mutant A53T -synuclein (line M83) are unlike those from human brains. They are more similar to the multiple system atrophy folds than to the Lewy fold of Parkinsons disease, Parkinsons disease dementia and dementia with Lewy bodies

biophysics↗

bioRxiv2025

Persistent articular infection and host reactive response contribute to Brucella-induced spondyloarthritis in SKG mice

Brucellosis, one of the most prevalent zoonotic diseases worldwide, often results in osteoarticular complications including large joint and axial arthritis mimicking spondyloarthritis. To model this chronic manifestation, we infected autoimmunity-prone SKG mice containing a mutation in the T-cell adaptor ZAP-70 with Brucella species. B. melitensis infection resulted in a fully penetrant, readily scoreable disease involving large joint wrist and foot arthritis, peri-ocular inflammation, and less frequent scaly paw rash. Infection with B. abortus resulted in delayed arthritis onset, and B. neotomae revealed sex differences, with more severe disease and a dose response in females. Heat-killed Brucella did not induce arthritis, evincing a requirement for viable infection. Across species, splenic CFU correlated well with final clinical score at 12 weeks ({rho}=0.79 and p<0.001). In vivo imaging using luminescent B. neotomae revealed rapid colonization of the paws by one-week post-infection, more than a month prior to arthritis onset. Paw luminescence levels decreased after 2 weeks and then remained relatively static, even as clinical scores increased. Thus, the degree of arthritis did not strictly correlate with degree of paw infection but suggested an additional reactive component. Further, in examining a Brucella {Delta}tcpB mutant lacking a Type IV secretion system-dependent mediator, mice displayed an intermediate phenotype without significant differences in splenic CFU. Together these data suggest Brucella induced spondyloarthritis reflects both persistent colonization as well as excess host reactivity. Moreover, the sensitivity of the SKG model to different species and mutants will provide new opportunities for dissecting correlates of Brucella virulence and host immunity. ImportanceBrucellosis, a bacterial infection acquired from herd animals, remains one of the most common zoonotic diseases worldwide. Chronic infection often results in spondyloarthritis-like complications. Investigation into pathogenesis has been limited by the lack of overt disease in standard lab mice. We addressed this issue using spondyloarthritis-susceptible SKG mice. Upon infection with B. melitensis, SKG mice develop robust, fully penetrant large joint arthritis. Arthritis development required viable bacteria. Moreover, studies of colonization, gene expression and anatomic distribution using bioluminescent bacteria revealed active persistent infection in the mouse paws. However, peak paw infection occurred much earlier than arthritis onset, suggesting an added immune reactive component. Disease onset, severity and manifestations varied upon infection with different Brucella species and mutants. Together these results suggest this new model will be very useful to the scientific community for determining correlates of bacterial virulence leading to clinical disease.

microbiology↗

bioRxiv2024

Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes

RNA editing is a post transcriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte specific, ADAR1 mediated RNA editing in neuroinflammation in Parkinsons disease. We generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with TLR activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions, and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to upregulation, and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in post-mortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinsons.

neuroscience↗

bioRxiv2019

jULIEs: extracellular probes for recordings and stimulation in the structurally and functionally intact mouse brain

High signal-to-noise, scalable and minimally invasive recording and stimulation of the nervous system in intact animals is of fundamental importance to advance the understanding of brain function. Extracellular electrodes are among the most powerful tools capable of interfacing with large neuronal populations1-3. Neuronal tissue damage remains a major limiting factor in scaling electrode arrays, and has been found to correlate with electrode diameter across different electrode materials, such as microfabricated Michigan and Utah-style arrays4, MEMS and microsystems5, soft polymer or tungsten electrodes6 and Parylene C probes7. Small diameter ultramicroelectrodes (UMEs), while highly desirable, pose significant technical challenges such as reaching sufficient electrolyte-electrode coupling and limiting stray signal loss. To overcome these challenges, we have designed juxtacellular Ultra-Low Impedance Electrodes (jULIEs), a scalable technique for achieving high signal-to-noise electrical recordings as well as stimulation with UMEs. jULIEs are metal-glass composite UMEs thermally drawn to outer diameters (OD) of <25 {micro}m, with metal core diameters (ID) of as little as 1 {micro}m. We introduce a two-step electrochemical modification strategy that reduces UME coupling impedances by two orders of magnitude. Modifications enabled high signal-to-noise neural recordings in vivo through wires with micrometer scale core diameters. Histological and imaging experiments indicated that local vascular damage is minimal. Spikes reached amplitudes over 1 mV in vivo, indicating that recordings are possible in close proximity to intact neurons. Recording sites can be arranged in arbitrary patterns tailored to various neuroanatomical target structures and allowing parallel penetrations. jULIEs thus represent a versatile platform that allows for reliable recording and manipulation of neural activity in any areas of the functionally intact mammalian brain.

neuroscience↗

bioRxiv2018

The BRadykinesia Akinesia INcoordination (BRAIN) tap test: capturing the sequence effect

BackgroundThe BRAIN tap test is an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinsons disease (PD).\n\nObjectivesTo develop a new parameter which detects a sequence effect and to reliably distinguish between PD patients on and off medication. Alongside, we sought to validate a mobile version of the test for use on smartphones and tablet devices.\n\nMethodsBRAIN test scores in 61 patients with PD and 93 healthy controls were compared. A range of established parameters captured speed and accuracy of alternate taps. The new VS (Velocity Score) recorded the inter-tap speed. Decrement in the VS was used as a marker for the sequence effect. In the validation phase, 19 PD patients and 19 controls were tested using multiple types of hardware platforms including smart devices.\n\nResultsQuantified slopes from the VS demonstrated bradykinesia (sequence effect) in PD patients (slope cut-off -0.002) with sensitivity of 58% and specificity of 81% (discovery phase of the study) and sensitivity of 65% and specificity of 88% (validation phase). All BRAIN test parameters differentiated between on medication and off medication states in PD. Most BRAIN tap test parameters had high test-retest reliability values (ICC>0.75). Differentiation between PD patients and controls was possible on all hardware versions of the test.\n\nConclusionThe BRAIN tap test is a simple, user-friendly and free-to-use tool for assessment of upper limb motor dysfunction in PD, which now includes a measure of bradykinesia.

neuroscience↗