Biology subjects

Matsubara, T.

Publications and source records attributed to Matsubara, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Signal-to-noise ratio of event-related fields in on-scalp and off-scalp MEG

Abstract Optically pumped magnetometer (OPM) sensors can be placed closer to the scalp than conventional superconducting quantum interference devices (SQUID), resulting in larger magnetoencephalography (MEG) signals from neuronal activity. For event-related sensor data, such as epileptogenic activity or sensory and motor evoked responses, however, OPMs and SQUIDs often differ less in signal-to-noise ratio (SNR) than in signal magnitude. We examined two factors contributing to the relative SNR: the dependence of the signal magnitude on source depth and the effect of scalp-to-sensor distance on the noise level. Simulated MEG data for a current dipole in a spherical head model confirmed that on-scalp sensor placement delivers the largest SNR gain for superficial sources. Depending on the relative overall noise level, there may be a crossover source depth at which SNR is equal for on-scalp and off-scalp sensors and beyond which off-scalp sensors achieve higher SNR. Analysis of the equal-SNR source depth in different-sized spherical head models indicated that, for a given relative noise level, the proportion of the brain where SNR is higher in OPM than in SQUID was larger in small head models, supporting the benefits of OPMs in pediatric studies. To experimentally evaluate noise contributions of brain and non-brain origin to the SNR, we recorded somatosensory evoked fields (SEFs) at varying scalp-to-sensor distances. Generally, both the evoked response magnitude and the noise level were lower when the sensors were further away from the scalp; consequently, the SNR depended less than the signal magnitude on the scalp-to-sensor distance. Comparison of power spectral densities (PSDs) at different sensor-to-scalp distances allowed us to identify whether the dominant noise source was of brain or non-brain origin at different frequency bands. Overall, the results highlight complementary properties of OPMs vs. SQUIDs in terms of SNR, which is of interest when optimizing MEG experiments for specific subject populations and brain regions.

neuroscience↗

bioRxiv2026

Motion tolerance in wearable OPM-MEG using dynamic field nulling

Wearable magnetoencephalography (MEG) enabled by optically pumped magnetometers (OPMs) promises improved comfort and motion tolerance. This is particularly beneficial when measuring brain activity in children who cannot sit still for long periods of time. Compared to cryogenic MEG, wearable MEG allows larger head movements, but they result in artifacts due to uncompensated background fields and reduce source localization accuracy. Spatial filtering methods can partially compensate these motion-induced artifacts, but they are most effective when used in combination with background field nulling. This is because accurate spatial filtering relies on an accurate estimate of the sensor gain and orientation of its sensitive axis. Through simulations, we first deduce the target residual background field that is necessary for accurate dipole localization (< 1 cm) in the presence of head movements. Using our open-source printed circuit board (PCB) coils, we develop a method to dynamically null the background field. We demonstrate that our dynamic field nulling method allows improved localization of somatosensory evoked fields (SEFs) by maintaining the background field below the target residual fields established in the simulations. Our study highlights the importance of tracking both the background field and the head position relative to the background field for quality assurance in wearable MEG.

neuroscience↗

bioRxiv2026

Sex Differences in Physiological Hair Cycling and Adhesive Material-Induced Hair Regeneration in Mice

Sex differences in hair growth are clinically evident, but sex-dependent regulation of physiological hair cycling and injury-induced hair regeneration remains incompletely understood. We compared physiological dorsal hair-cycle progression and adhesive material-induced localized hair regeneration in male and female C3H/He mice. Males entered the second and third anagen phases earlier than females, indicating longer telogen phases in females. In contrast, localized hair regrowth after application and removal of a cyanoacrylate adhesive material appeared earlier in females. Ovariectomy induced widespread telogen-to-anagen transition and therefore did not permit isolation of ovarian-hormone effects on the localized response. RNA sequencing of intact dorsal skin identified sex-dependent baseline expression profiles involving inflammation, wound response, and tissue repair. Independent time-course quantitative PCR further demonstrated sex-dependent expression of inflammatory and reparative genes after adhesive material application. Local clodronate liposome administration alone induced delayed perifocal hair growth. When combined with adhesive material application, clodronate treatment markedly delayed wound healing and localized hair regrowth in males, whereas these responses were comparatively preserved in females. These findings show that physiological hair cycling and adhesive material-induced hair regeneration exhibit distinct sex differences and suggest that the localized regenerative response is more macrophage-dependent in males than in females.

developmental biology↗

bioRxiv2026

Regional Differences in Dorsal Skin Determine the Rate of Adhesive Material-Induced Hair Regeneration

Dorsal skin is widely used in mouse wound-healing, dermatitis, and hair-cycle models, but is often treated as a uniform site. We investigated whether adhesive material (cyanoacrylate)-induced hair regeneration, a model we previously reported, differs by position within the dorsal skin. Adhesive material was applied to four regions along the cranial-to-caudal axis of the mouse dorsal skin. Hair regrowth appeared earlier at the cranial sites than at the caudal sites, and this difference persisted through late anagen and the anagen-to-catagen transition. In contrast, hair regrowth after full-thickness skin excision was slower, smaller in area, and less reproducible than that after adhesive material application. Expression of Hox genes, including Hoxa9, Hoxb9, Hoxc9, Hoxa10, and Hoxc10, was higher at the caudal sites than at the cranial sites but did not correlate with the timing of hair regrowth. RNA sequencing of intact skin from the cranial and caudal sites revealed distinct baseline profiles, including differences in the Wnt inhibitor Sfrp4 and the adipogenic genes Ppar{gamma} and Fabp4. Early after adhesive material application, histological changes and the expression of inflammation- and tissue-repair-related genes also differed between the cranial and caudal skin. These findings indicate that mouse dorsal skin is not a uniform experimental field and that cranial-to-caudal position should be considered when designing and interpreting hair-regeneration and wound-healing experiments in mice.

developmental biology↗

bioRxiv2026

Quantifying Cerebellar Signal Detectability in MEG and EEG in Epilepsy Using Anatomically Informed Source Modeling

ObjectiveThe cerebellum is increasingly recognized as a key component of large-scale brain networks implicated in epilepsy, yet its electrophysiological characterization remains limited in noninvasive recordings. This limitation arises from the cerebellums depth, complex folding, and unfavorable source orientations, which challenge conventional magnetoencephalography (MEG) and electroencephalography (EEG). Here, we quantitatively characterize cerebellar signal detectability across modalities and sensor configurations using anatomically informed source modeling at the population level. MethodsWe analyzed clinical MEG and EEG recordings from a large cohort of patients with epilepsy undergoing presurgical evaluation. Cerebellar and cerebral source spaces were constructed using subject-specific anatomical models derived from routine clinical MRI, enabling consistent forward modeling across individuals. Signal-to-noise ratio (SNR) was estimated at individual source locations and summarized at the regional level. In addition to clinical Superconducting quantum interference device (SQUID)-MEG and EEG, multiple on-scalp optically pumped magnetometer (OPM) configurations were evaluated through simulation, including layouts matched to clinical sensor geometries and layouts optimized for posterior fossa coverage. The effects of source orientation, sensor-source distance, and head size on SNR were systematically investigated. ResultsIn routine clinical recordings, cerebellar SNR was consistently lower than superficial cortical reference levels, confirming the limited detectability of cerebellar activity with standard SQUID-MEG and EEG. Reducing sensor-source distance by placing OPMs at SQUID-equivalent locations, i.e., projecting SQUID sensor locations to the scalp, did not improve cerebellar SNR, indicating that proximity alone is insufficient for better detectability of deeper sources. In contrast, cerebellar-optimized OPM layouts produced substantial SNR gains in posterior cerebellar regions. The effects of source orientation influence SNR differences between OPM and EEG (under identical sensor/electrode coverage) but were secondary to depth- and geometry-related constraints. Mediation analysis further demonstrated that relative sensor distance significantly mediated OPM-related advantages in posterior cerebellar regions, particularly in individuals with smaller head sizes. ConclusionsThese findings demonstrate that cerebellar signal detectability is governed primarily by anatomical depth and geometry rather than sensor proximity alone. Anatomically informed source modeling, combined with flexible and region-specific sensor layouts, enables meaningful improvements in cerebellar SNR that are not achievable with fixed-helmet systems. While directly motivated by epilepsy, this framework advances human brain mapping beyond the cerebrum by providing a principled approach for evaluating MEG and EEG sensitivity in deep and highly folded brain structures.

bioengineering↗

bioRxiv2025

LRBA promotes drug-induced liver injury and MASLD by scaffolding MAPK activation

LPS-responsive beige-like anchor protein (LRBA) regulates vesicular trafficking and receptor recycling, and its deficiency results in immunodeficiency characterized by hypogammaglobulinemia and autoimmune syndrome. However, its role in liver pathophysiology remains unclear. Here, we reveal a previously unrecognized function of LRBA as a critical intracellular scaffold for mitogen-activated protein kinase (MAPK) activation that promotes liver injury. Lrba-/-mice exhibit reduced acetaminophen (APAP)-induced hepatic necrosis through the suppression of JNK activation. In a model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by a high-fat, high-cholesterol (HFHC) diet, Lrba deficiency reduces hepatic inflammation, fibrosis, and Kupffer cell activation. Mechanistically, LRBA homodimers directly interact with specific mitogen-activated protein kinase kinase kinases (MAP3Ks), including transforming growth factor-{beta}-activated kinase 1 (TAK1) and mixed-lineage kinase 3 (MLK3), to facilitate their activation. LRBA, which is primarily expressed in hepatocytes under physiological conditions, is upregulated in non-parenchymal cells such as Kupffer cells and cholangiocytes in both HFHC diet-fed mice and patients with MASLD and cirrhosis, linking its scaffolding function to pathological inflammation. Thus, LRBA promotes liver disease progression by amplifying inflammatory signaling.

cell biology↗

bioRxiv2025

Analysis of the phosphorylation networks characterizing distinct phenotypic states in glioblastoma cell Populations

Cancer cells, including the most aggressive brain cancer, glioblastoma, can exhibit a high degree of phenotypic plasticity. However, it is not well understood whether and how distinct phenotypic states might be associated with or driven by specific signaling processes. Here, we use a novel approach to the identification of phenotype-specific signaling networks in cells undergoing the Go-or-Grow switch in populations of GBM cell lines. We find that the transition to invasive spread may be associated with the onset of DNA damage response, cell cycle arrest, and activation of the AKT-mTOR signaling. We reconstructed the large-scale signaling networks, revealing integration of diverse pathways and possible feedback interactions mediating phenotypic stability. We further show that phosphorylation outcomes may be preferentially mediated by 14-3-3 proteins, previously implicated in stress response and control of the cell cycle. Finally, we demonstrate that the phenotype-specific phospho-site signatures have predictive power for disease-free patient survival. This study paves the way for a more comprehensive understanding of phenotypic plasticity in GBM and other aggressive cancers.

systems biology↗

bioRxiv2025

A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis

Liver fibrosis progression and regression are dynamic processes involving diverse hepatic and immune cell populations. Here, we utilize single-cell fixed RNA profiling (FLEX) of a TAA-induced mouse liver cirrhosis model, with and without a recovery phase, to depict the cellular landscape and molecular mechanisms of fibrosis resolution. The regression phase was characterized by the emergence of pericentral hepatocytes enriched in detoxification and antioxidant genes (e.g., Cyp2e1, Txn1), which secreted Rarres2 to modulate hepatic stellate cell (HSC) function. This was accompanied by the upregulation of scar-resolving genes (Mmp14, Ctsl), restoration of fenestrae in liver sinusoidal endothelial cells, anti-inflammatory phenotypes of Kupffer cells, a decrease in fibrogenic cholangiocyte subsets, and recovery-associated signatures in NK/T cells, B cells, and neutrophils. In contrast, SEMA4D secreted by monocyte-derived macrophages during fibrosis progression activated Plxnb2 HSCs, and its blockade attenuated fibrosis in vivo. Furthermore, LMCD1 was identified as a novel marker for HSC activation and regulation. This single-cell atlas reveals key transcriptional programs and intercellular signaling pathways dependent on the fibrotic condition, offering new therapeutic targets for liver cirrhosis.

cell biology↗

bioRxiv2025

Biplanar nulling coil system for OPM-MEG using printed circuit boards

Optically pumped magnetometers (OPMs) are a promising sensor technology for non-invasive measurement of human electrophysiological signals, in particular the magnetoencephalogram (MEG). OPMs do not need cryogenic cooling and can be placed conformal to the subjects scalp, thus greatly reducing the sensor-to-source distance and improving signal sensitivity. OPMs, however, require near-zero background magnetic field to achieve linearity and minimize signal distortion. Prior work has proposed the use of biplanar field nulling coils to remove the uniform and gradient components of the background magnetic field. Biplanar coils have been expensive to construct, involving tedious error-prone manual winding of over 1000 m of copper wire. In this work, we designed and fabricated background field nulling coils (three uniform and three gradient components) on two-layer Printed Circuit Boards (PCBs). We used an open-source software (bfieldtools) to determine the current loops needed to produce the target magnetic field in a 50-cm-diameter spherical volume. We developed a software-based approach to connect the discrete current loops into a continuous conducting path traversing the two layers of the PCB. For ease of manufacture, the designed (1.5 x 1.5 m2) coils were cut along the symmetry axis and printed as pairs of 1.5 x 0.75 m2 PCBs (2 oz Cu), soldered together and mounted on a sliding aluminum frame. The efficiency of the coils (1.3 - 7.1 nT/mA) was similar or higher than previously reported in the literature. We mapped the field inside the target region after field nulling inside our single-layer shielded room and were able to reduce the largest component of the background field from 21 to 2 nT. Using our nulling coil system, we were able to operate OPMs in a lightly shielded room (background field varying from 6.5 to 108 nT in the floor-to-ceiling direction) to record somatosensory evoked fields (SEFs) comparable to those measured using SQUID-based MEG in a 3-layer shielded room. We disseminate the software and hardware as an open-source package opmcoils. This work will facilitate access to more affordable field nulling coils for OPM-MEG and help to realize the potential of OPM-MEG as an accessible sensor technology for use in human neuroscience.

neuroscience↗

bioRxiv2024

Wound-initiated hair regeneration by adhesive and shrinkable materials

Although there is a global demand for hair regrowth, particularly among middle-aged and older individuals, an effective hair growth technology has not yet been established1. Hair follicle neogenesis is restricted to the embryonic period, but hair regeneration accompanied by wound healing has been observed under some conditions2-4; however, the underlying mechanisms are unclear. Herein, we demonstrated that creating a wound without dermal defects effectively induced postneonatal hair follicle neogenesis. Separating the epidermis from the dermis by topical application of adhesive and shrinkable materials to mouse skin promoted epidermal regeneration, followed by new hair follicle formation. Hair follicle regeneration, accompanied by the upregulation of related genes, can be induced in mice, including middle-aged and aged mice, regardless of species, sex, skin location, or age. The cycle of the regenerated hair eventually synchronized with that of the surrounding physiological hairs. Our new hair regeneration technique based on reproduction of epidermis-dermis interactions provides a novel means to treat hair loss, including androgenetic alopecia.

cell biology↗

bioRxiv2024

Comprehensive evaluation of pipelines for diagnostic biomarkers of major depressive disorder using multi-site resting-state fMRI datasets

The objective diagnostic and stratification biomarkers developed with resting-state functional magnetic resonance imaging (rs-fMRI) data are expected to contribute to more effective treatment for mental disorders. Unfortunately, there are currently no widely accepted biomarkers, partially due to the large variety of analysis pipelines for developing them. In this study we comprehensively evaluated analysis pipelines using a large-scale, multi-site fMRI dataset for major depressive disorder (MDD) (1162 participants from eight imaging sites). We explored the combinations of options in four subprocesses of analysis pipelines: six types of brain parcellation, four types of estimations of functional connectivity (FC), three types of site difference harmonization, and five types of machine learning methods. 360 different MDD diagnostic biomarkers were constructed using the SRPBS dataset acquired with unified protocols (713 participants from four imaging sites) as a discovery dataset and evaluated with datasets from other projects acquired with heterogeneous protocols (449 participants from four imaging sites) for independent validation. To identify the optimal options regardless of the discovery dataset, we repeated the same procedure after swapping the roles of the two datasets. We found pipelines that included Glassers parcellation, tangent-covariance, no harmonization, and non-sparse machine learning methods tended to result in high classification performance. The diagnosis results of the top 10 biomarkers showed high similarity, and weight similarity was also observed between eight of the biomarkers, except two that used both data-driven parcellation and FC computation. We applied the top 10 pipelines to the datasets of other mental disorders (autism spectral disorder: ASD and schizophrenia: SCZ) and eight of the ten biomarkers showed sufficient classification performances for both disorders, except two pipelines that included Pearson correlation, ComBat harmonization and random forest classifier combination. HighlightsO_LIWe evaluated the analysis pipelines of rsFC biomarker development. C_LIO_LIFour subprocesses in them were investigated with two multi-site datasets. C_LIO_LIGlassers parcellation, tangent covariance, and non-sparse methods were preferred. C_LIO_LIThe weight patterns of eight of the top 10 biomarkers showed high commonality. C_LIO_LIEight of the top 10 pipelines were successful for developing SCZ/ASD biomarkers. C_LI

neuroscience↗

bioRxiv2022

Primary motor cortex drives expressive facial movements related to reward processing in mice

During reward-based learning tasks, animals make orofacial movements that globally influence brain activity at the timings of reward expectation and acquisition. These orofacial movements are not explicitly instructed and typically appear along with goal-directed behaviors. Here we show that reinforcing optogenetic stimulation of midbrain dopamine neurons (oDAS) in mice is sufficient to induce orofacial movements in the whiskers and nose without accompanying goal-directed behaviors. Pavlovian conditioning with a sensory cue and oDAS elicited cue-locked and oDAS aligned orofacial movements, which were distinguishable by a machine learning model. Inhibition or knock-out of dopamine D1 receptors in the nucleus accumbens inhibited oDAS-induced motion but spared cue-locked motion, suggesting differential neural regulation of these two types of orofacial motions. In contrast, inactivation of the whisker primary motor cortex (wM1) abolished both types of orofacial movements. We found specific neuronal populations in wM1 representing either oDAS-aligned or cue-locked whisker movements. Notably, optogenetic stimulation of wM1 neurons successfully replicated these two types of movements. Our results thus suggest that accumbal D1 receptor-dependent and -independent neuronal signals converge in the wM1 for facilitating uninstructed orofacial movements during a reward-based learning task.

neuroscience↗

bioRxiv2022

Proteomic profile of nuclei containing p62-positive inclusions in neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Intranuclear inclusions are the pathological hallmark of NIID. Previously, immunohistochemistry has revealed that intranuclear inclusions are ubiquitin-, p62-, and SUMO-1-positive, suggesting the possible alteration of the ubiquitin-proteasomal protein degradation system in the nuclei with inclusions. However, the molecular mechanisms within these nuclei remain unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in NIID with CGG repeat expansion in NOTCH2NLC to discover the proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins in the autopsy brain samples from three NIID patients was confirmed via immunofluorescence. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A3, hnRNP A2/B1, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than those without; however, they were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. These data can form the basis for understanding the pathophysiology of NIID.

biochemistry↗

bioRxiv2022

Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs

-Synuclein (Syn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric Syn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric Syn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating Syn fibril morphology, providing significant insights into the fibrogenesis of Syn. Significance StatementThe Syn C-terminus domain acts as the master switch programming its fibril polymorphism.

biophysics↗

bioRxiv2021

Role of TLR4 signaling on Porphyromonas gingivalis LPS-induced cardiac dysfunction in mice

Oral infections, particularly periodontitis, are a well-established risk factor for cardiovascular diseases, although the molecular mechanisms involved remain elusive. The aims of the present study were to investigate the effects of lipopolysaccharide derived from Porphyromonas gingivalis (PG-LPS) on cardiac function in mice, and to elucidate the underlying mechanisms. Mice (C57BL/6) were injected with PG-LPS (0.8 mg/kg/day) with or without an inhibitor of Toll-like receptor 4 (TLR4) signaling (TAK-242, 0.8 mg/kg/day) for 4 weeks. Left ventricular ejection function was significantly decreased at 1 week (from 67 {+/-} 0.5 to 58 {+/-} 1.2 %) and remained low at 4 weeks (57 {+/-} 1.0 %). The number of apoptotic myocytes was increased (approximately 7.4-fold), the area of fibrosis was increased (approximately 3.3-fold) and the number of 8-hydroxydeoxyguanosine-positive myocytes, a sensitive indicator of oxidative DNA damage, was increased (approximately 7.6-fold) at 4 weeks in the heart of PG-LPS treated mice. However, levels of various serum pro-inflammatory cytokines in PG-LPS-treated mice were similar to those in control mice. The impairment of cardiac function in PG-LPS-treated mice appears to involve activation of TLR4-NADPH oxidase (NOX) 4 signaling, leading to abundant production of reactive oxygen species and Ca2+ leakage from sarcoplastic reticulumn induced by calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (at Thr-17) and ryanodine receptor 2 (at Ser-2448). Pharmacological inhibition of TLR4 with TAK-242 attenuated the changes in cardiac function in PG-LPS-treated mice. Our results indicate that TLR4-NOX4 signaling may be a new therapeutic target for treatment of cardiovascular diseases in patients with periodontitis.

physiology↗

bioRxiv2020

Structures of α-synuclein filaments from multiple system atrophy

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinsons disease, Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of -synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of -synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that -synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that -synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4-9), the structures of -synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous -synuclein inclusions in human brain.

neuroscience↗

bioRxiv2019

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1-3). A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4, 5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7, 8), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11-15). This distinguishes 4R tauopathies from Picks disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimers disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimers disease, Picks disease and CTE (17-19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

neuroscience↗

bioRxiv2019

Remote control of neural function by X-ray-induced scintillation

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), could effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles were non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level was sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables less invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.

neuroscience↗