A5033546515- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Alzheimer's disease research and treatments
- Genetic Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Nuclear Receptors and Signaling
- Neurological disorders and treatments
- Photochromic and Fluorescence Chemistry
- Endoplasmic Reticulum Stress and Disease
- Retinoids in leukemia and cellular processes
- Autism Spectrum Disorder Research
- Toxin Mechanisms and Immunotoxins
- Lipid metabolism and biosynthesis
- Cholinesterase and Neurodegenerative Diseases
- Synthesis and Characterization of Heterocyclic Compounds
- Microtubule and mitosis dynamics
- Photosynthetic Processes and Mechanisms
- Fungal and yeast genetics research
- Biotin and Related Studies
- Ginkgo biloba and Cashew Applications
- biodegradable polymer synthesis and properties
- Dendrimers and Hyperbranched Polymers
- Neurological diseases and metabolism
- Lysosomal Storage Disorders Research
- Neurological Disease Mechanisms and Treatments
Harvard University
2017-2025
Brigham and Women's Hospital
2020-2025
Howard Hughes Medical Institute
2017
Princeton University
2009
St. Stephen’s Hospital
2001
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...
Tau and α-synuclein aggregates are the main histopathological hallmarks present in Alzheimer's disease (AD), Parkinson's (PD), other neurodegenerative disorders. Intraneuronal hyperphosphorylated tau accumulation is significantly connected to degree of cognitive impairment AD patients. In particular, longest 2N4R isoform has a propensity rapidly form oligomers mature fibrils. On hand, misfolding (α-syn) characteristic feature PD dementia with Lewy bodies (DLB). There strong crosstalk between...
Abstract Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration familial Parkinson’s disease (fPD). However, most mouse models expressing single-mutant transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD E46K mutant mice with rationally designed triple mutations based on α-helical repeat motif structure (fPD E46K→3...
α-Synuclein (αS) plays a key role in Parkinson's disease. Although disease is typically “sporadic,” inherited αS missense mutations provide crucial insights into molecular mechanisms. Here, we examine two clinical mutants, E46K and G51D, which are both the conserved N-terminus that mediates transient αS-membrane interactions. However, increases G51D decreases Previously, amplified via 11-residue repeat motifs, creating “3K” (E35K+E46K+E61K). engineered these motifs to amplify (V40D+G51D+V66D...
Genetic and biochemical evidence attributes neuronal loss in Parkinson's disease (PD) related brain diseases to dyshomeostasis of the 14 kDa protein α-synuclein (αS). There is no consensus on how αS exerts toxicity. Explanations range from disturbed vesicle biology proteotoxicity caused by fibrillar aggregates. To probe these mechanisms further, robust cellular toxicity models are needed, but their availability limited. We previously reported that a shift dynamic multimers monomers an early...
Alzheimer's (AD) and Parkinson's (PD) disease are neurodegenerative disorders that considered to be a significant global health challenge due their increasing prevalence profound impact on both individuals society. These characterized by the progressive loss of neuronal function, leading cognitive motor impairments. A key pathological feature AD PD is abnormal accumulation misfolded proteins within brain. In AD, amyloid-beta aggregates into plaques, while tau form neurofibrillary tangles...
Protein misfolding results in a plethora of known diseases such as Alzheimer’s disease, Parkinson’s Huntington’s transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide diverse portfolio therapeutic small molecules with the ability to reduce protein misfolding, we evaluated set 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), triazine (5) linker. In...
Alzheimer's disease (AD) and Parkinson's (PD) are multifactorial, chronic diseases involving neurodegeneration. According to recent studies, it is hypothesized that the intraneuronal postsynaptic accumulation of misfolded proteins such as α-synuclein (α-syn) tau, responsible for Lewy bodies (LB) tangles, respectively, disrupts neuron functions. Considering co-occurrence α-syn tau inclusions in brains patients afflicted with subtypes dementia LB disorders, discovery development small...
Abstract α-Synuclein (αS) has been well-documented to play a role in human synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). First, the lesions found PD/DLB brains—Lewy neurites—are rich aggregated αS. Second, genetic evidence links missense mutations increased αS expression familial forms of PD/DLB. Third, toxicity cellular stress can be caused by under certain experimental conditions. In contrast, homologs β-synuclein (βS) γ-synuclein (γS) are not...
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...
Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing transcript levels largely...
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-β (Aβ) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half cases also display presence α-synuclein (α-syn)-containing Lewy bodies. Conversely, bodies disorders have been reported to concomitant Aβ...
The neuronal protein α‐synuclein is centrally involved in the neurodegeneration occurring Parkinson's disease and related synucleinopathies. α‐Synuclein's membrane‐induced 3–11 helix conformation has a hydrophobic membrane‐embedded half hydrophilic cytosolic half. Here, we studied significance of (a) surprising hydrophobicity amino‐acids at cytosol‐exposed position 8; (b) absence positively charged lysine/arginine from all positions (1‐5‐8‐9). We found that further increasing or adding...
Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer's disease (AD), Lewy body dementia (LBD), Parkinson's (PD) patients. The early-stage oligomers protofibrils tau believed to strongly linked human cognitive impairment while toxic α-syn associated with behavioral motor deficits. Therefore, concurrent targeting both proteinaceous aggregates very challenging. Herein, rhodanine-based compounds were...
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting elderly population worldwide. In PD, misfolding of α-synuclein (α-syn) results in formation inclusions referred to as Lewy bodies (LB) midbrain neurons substantia nigra and other specific brain localizations, which associated with neurodegeneration. There are no approved strategies reduce LB patients PD. Our drug discovery program focuses on synthesis urea thiourea compounds coupled aminoindole moieties...