A5084102235- Parkinson's Disease Mechanisms and Treatments
- Nuclear Receptors and Signaling
- Neurological diseases and metabolism
- Genetic Neurodegenerative Diseases
- Neurological disorders and treatments
- Molecular Biology Techniques and Applications
- Cell Image Analysis Techniques
- Medicinal Plants and Bioactive Compounds
- Functional Brain Connectivity Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- DNA Repair Mechanisms
- Light effects on plants
- Connective tissue disorders research
- Amyotrophic Lateral Sclerosis Research
- Multiple Sclerosis Research Studies
- Aquatic life and conservation
- Alzheimer's disease research and treatments
- Brain Tumor Detection and Classification
- Monoclonal and Polyclonal Antibodies Research
- Coenzyme Q10 studies and effects
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Advanced Biosensing Techniques and Applications
- Protein Hydrolysis and Bioactive Peptides
- Cytomegalovirus and herpesvirus research
Brigham and Women's Hospital
2022-2025
Harvard University
2022-2025
Innsbruck Medical University
2019-2024
Universität Innsbruck
2019-2024
American Parkinson Disease Association
2024
Research Network (United States)
2024
Abstract RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous terms of age onset, disease progression and phenotype. We investigated the role size influencing clinical variables disease. also assessed presence meiotic somatic instability repeat. In this study, we identified 553 patients carrying expansions measured 392 cases. Pearson’s coefficient was calculated to assess correlation between at onset. A Cox model with robust cluster standard errors adopted...
Highlights•Generation of a foundational genomic resource in multiple system atrophy•GWAS identifies novel risk loci at GAB1, lnc-LRRC49-3, TENM2, and RABGEF1•Functional genomics implicates USP38-DT, KCTD7, lnc-KCTD7-2 within these loci•Gene-burden analysis nominal enrichment rare missense mutations KCTD7SummaryMultiple atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, dysautonomia. The genetic architecture MSA poorly understood,...
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop neither reproducibly nor a reasonable time frame. Here, we developed screenable "inclusionopathy" utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions their effects on cell survival were trackable single-inclusion resolution. Exemplar cortical neuron...
The quantification and characterization of aggregated α-synuclein in clinical samples offer immense potential toward diagnosing, treating, better understanding neurodegenerative synucleinopathies. Here, we developed digital seed amplification assays to detect single aggregates by partitioning the reaction into microcompartments. Using pre-formed fibrils as seeds, measured aggregate concentrations low 4 pg/mL. To improve our sensitivity, captured on antibody-coated magnetic beads before...
Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson’s disease related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map regulatory network that controls endogenous using sequential CRISPR-knockout -interference screens in an gene ( SNCA )–tagged cell line induced pluripotent stem cell–derived neurons (iNeurons). We uncover modifiers at multiple layers, amino-terminal...
Summary The pathological hallmark of neurodegenerative disease is the aberrant post-translational modification and aggregation proteins leading to formation insoluble protein inclusions. Genetic factors like APOE4 are known increase prevalence severity tau, amyloid, α-Synuclein However, human brain largely inaccessible during this process, limiting our mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, cerebrovascular cells into a...
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative disorder caused by intronic biallelic, nonreference CCCTT/AAGGG repeat expansions within RFC1 . To investigate how these repeats cause disease, we generated patient induced pluripotent stem cell–derived neurons (iNeurons). do not alter neuronal splicing, expression, or DNA repair pathway function. In reporter assays, AAGGG are translated into pentapeptide proteins....
ABSTRACT Intracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models, while promising for disease modeling, do not form in a reasonable timeframe suffer from limited tractability. Here, we developed an toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression aggregation-prone proteins. This system amenable screening...
Abstract Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson’s (PD), rapid progression have sparked interest drug development. One significant obstacle therapeutics heterogeneity. Here, we share our process developing clinical trial-ready cohort MSA patients (69 2 years) within an outpatient setting, recruiting 20...
PFF seeding in U2OS cells
Induced astrocyte differentiation
Generation of preformed αS fibrils
Quantitative PCR for STMN2 expression in pi-N neurons
Seeded amplification assay (SAA) from neuronal cell lysates
Stable integration of piggyBac plasmids into U2OS cells
Whole cell protein extraction and Western blotting
Western blot of amplified fibrils after Proteinase K digestion
Seeded amplification assay (SAA) from neuronal cell or postmortem brain lysates
PFF seeding in iPSC-derived cortical neurons_reformatted