A5040726643- Single-cell and spatial transcriptomics
- Neuroinflammation and Neurodegeneration Mechanisms
- Alzheimer's disease research and treatments
- Cancer Genomics and Diagnostics
- MicroRNA in disease regulation
- Parkinson's Disease Mechanisms and Treatments
- RNA Research and Splicing
- Pancreatic and Hepatic Oncology Research
- Cancer Cells and Metastasis
- Spaceflight effects on biology
- RNA regulation and disease
- Immune cells in cancer
- Neurogenesis and neuroplasticity mechanisms
- Gene Regulatory Network Analysis
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Trace Elements in Health
- Gene expression and cancer classification
- Cell Image Analysis Techniques
- Platelet Disorders and Treatments
- Extracellular vesicles in disease
- Vestibular and auditory disorders
- Molecular Biology Techniques and Applications
- Bioinformatics and Genomic Networks
- Advanced biosensing and bioanalysis techniques
- Genetic Neurodegenerative Diseases
Broad Institute
2009-2024
Massachusetts General Hospital
2012-2023
Harvard NeuroDiscovery Center
2010-2023
Harvard University
2010-2023
Stanley Center for Psychiatric Research
2018-2022
MaineGeneral Medical Center
2012-2022
Stanley Foundation
2020
Massachusetts Institute of Technology
2009-2020
Advanced Tissue (United States)
2006-2019
Pathfinder International
2019
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused sarcoma/translated liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions diverse processes, and normally located predominantly nucleus. In contrast, mutant forms accumulated cytoplasm neurons, pathology similar TAR DNA-binding 43...
Spatial positions of cells in tissues strongly influence function, yet a high-throughput, genome-wide readout gene expression with cellular resolution is lacking. We developed Slide-seq, method for transferring RNA from tissue sections onto surface covered DNA-barcoded beads known positions, allowing the locations to be inferred by sequencing. Using we localized cell types identified single-cell sequencing datasets within cerebellum and hippocampus, characterized spatial patterns Purkinje...
The transition between soluble intrinsically disordered tau protein and aggregated in neurofibrillary tangles Alzheimer's disease is unknown. Here, we propose that species can undergo liquid-liquid phase separation (LLPS) under cellular conditions phase-separated droplets serve as an intermediate toward aggregate formation. We demonstrate phosphorylated or mutant aggregation prone recombinant undergoes LLPS, does high molecular weight phospho-tau isolated from human Alzheimer brain....
Aggregation of alpha-synuclein (αsyn) and resulting cytotoxicity is a hallmark sporadic familial Parkinson's disease (PD) as well dementia with Lewy bodies, recent evidence implicating oligomeric pre-fibrillar forms αsyn the pathogenic species. Recent in vitro studies support idea transcellular spread extracellular, secreted across membranes. The aim this study to characterize oligomers determine their extracellular location.Using novel protein fragment complementation assay where fused...
To examine region- and substrate-specific autoradiographic in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow vivo detection paired helical filament-tau-containing lesions, determine whether there is off-target other amyloid/non-amyloid proteins.We applied phosphor screen autoradiography, nuclear emulsion [H-3]-AV-1451 assays the study postmortem samples from patients with a definite pathological diagnosis Alzheimer...
Charting an organs’ biological atlas requires us to spatially resolve the entire single-cell transcriptome, and relate such cellular features anatomical scale. Single-cell single-nucleus RNA-seq (sc/snRNA-seq) can profile cells comprehensively, but lose spatial information. Spatial transcriptomics allows for measurements, at lower resolution with limited sensitivity. Targeted in situ technologies solve both issues, are gene throughput. To overcome these limitations we present Tangram, a...
Here we report the generation of a multimodal cell census and atlas mammalian primary motor cortex as initial product BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved morphological electrophysiological properties cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance collective knowledge...
Abstract The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark Parkinson’s disease (PD). Nevertheless, molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed protocol to enrich and transcriptionally profile from patients PD matched controls, sampling total 387,483 nuclei, including 22,048 profiles. We identified ten populations spatially localized each SNpc using...
Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) recently discovered small regulatory RNA molecules that repress gene expression increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 miR-212, downregulated temporal cortical areas CA1 hippocampal neurons of AD brains....
Abstract Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in brain 1–3 . With proliferation multi-omics datasets, a major challenge is to validate and integrate results into biological understanding cell-type organization. Here we generated transcriptomes epigenomes from more than 500,000 individual cells mouse primary motor cortex, structure that has an evolutionarily conserved role locomotion. We developed...
Abstract The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However, complete inventory of cell types currently lacking. Here, using recent advances high-throughput transcriptional profiling 1–3 , we molecularly define across individual lobules the adult mouse cerebellum. Purkinje neurons showed considerable regional specialization, greatest diversity occurring posterior lobules. For several...
Exosomes are cellular secretory vesicles containing microRNAs (miRNAs). Once secreted, exosomes able to attach recipient cells and release miRNAs potentially modulating the function of cell. We hypothesized that exosomal miRNA expression in brains patients diagnosed with schizophrenia (SZ) bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations SZ BD patients. The sources analyzed samples included McLean 66 Cohort Collection (Harvard Brain...
Objective Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind tau lesions other tauopathies remains controversial. Our goal was examine correlation vivo and postmortem patterns three autopsy-confirmed non-Alzheimer tauopathy cases. Methods We quantified retention [F-18]-AV-1451 performed autoradiography, [H-3]-AV-1451...
Abstract The function of the mammalian brain relies upon specification and spatial positioning diversely specialized cell types. Yet, molecular identities types their positions within individual anatomical structures remain incompletely known. To construct a comprehensive atlas in each structure, we paired high-throughput single-nucleus RNA sequencing with Slide-seq 1,2 —a recently developed transcriptomics method near-cellular resolution—across entire mouse brain. Integration these datasets...
Abstract Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding how complex tissues are constructed 1–6 . However, missing from these measurements is ability to routinely easily spatially localize profiled cells. We developed a strategy, Slide-tags, in which single nuclei an intact tissue section tagged with spatial barcode oligonucleotides derived DNA-barcoded beads...
A three-dimensional (3-D) lung aggregate model was developed from A549 human epithelial cells by using a rotating-wall vessel bioreactor to study the interactions between Pseudomonas aeruginosa and cells. The suitability of 3-D aggregates as an infection examined immunohistochemistry, adherence invasion assays, scanning electron microscopy, cytokine mucoglycoprotein production. Immunohistochemical characterization showed increased expression cell-specific markers decreased cancer-specific...
Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of cerebral cortex. Mutations in either two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange 2 (ARFGEF2) , cause PH (Fox et al. ‘Mutations filamin 1 prevent migration cortical neurons periventricular heterotopia'. Neuron,21, 1315–1325, 1998; Sheen al . ARFGEF2 implicate vesicle trafficking neural progenitor proliferation and cortex'....
Iron influx increases the translation of Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE) RNA stem loop in its 5'-untranslated region. Equal modulated interaction iron regulatory proteins (IRP1 and IRP2) with canonical IREs controls iron-dependent ferritin subunits. However, our immunoprecipitation RT-PCR binding experiments demonstrated that IRP1, but not IRP2, selectively bound APP IRE human neural cells. This selective IRP1 pattern was evident brain blood...
The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts leukoencephalopathy (CADASIL), which associated mutations in Notch 3 receptor. CADASIL pathology characterized by smooth muscle cell degeneration accumulation diagnostic granular osmiophilic material (GOM) vessels. functional nature causing their mechanistic connection GOM remain...
[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer's disease (AD). PET studies have shown increased retention patients clinically diagnosed dementia of AD type and mild cognitive impairment regions that are known contain lesions. In vivo uptake has also consistently been observed midbrain, basal ganglia choroid plexus elderly individuals regardless their clinical diagnosis, including normal whose brains not...
Highlights•In silico predictions of miR-2392 as a miRNA involved with SARS-CoV-2•Overexpression produces similar biological response COVID-19 infection•miR-2392 is confirmed to circulate in serum and urine patients COVID-19•Development initiated potential antiviral therapeutic against COVID-19SummaryMicroRNAs (miRNAs) are small non-coding RNAs post-transcriptional gene regulation that have major impact on many diseases provide an exciting avenue toward therapeutics. From patient...