A5048570234- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Dementia and Cognitive Impairment Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Amyotrophic Lateral Sclerosis Research
- Neurological diseases and metabolism
- Genetic Neurodegenerative Diseases
- Bioinformatics and Genomic Networks
- Genetic Associations and Epidemiology
- Neuroscience and Neuropharmacology Research
- Nuclear Receptors and Signaling
- Neurological disorders and treatments
- Advanced Neuroimaging Techniques and Applications
- Mitochondrial Function and Pathology
- Cholinesterase and Neurodegenerative Diseases
- Traumatic Brain Injury and Neurovascular Disturbances
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- Tryptophan and brain disorders
- RNA regulation and disease
- Metabolomics and Mass Spectrometry Studies
- Drilling and Well Engineering
- Oil and Gas Production Techniques
- Epigenetics and DNA Methylation
- Neurological Disease Mechanisms and Treatments
Johns Hopkins University
2016-2025
Johns Hopkins Medicine
2016-2025
Johns Hopkins Hospital
1998-2024
University Medical Center
2019-2024
Hospital for Sick Children
2024
California University of Pennsylvania
2024
Rush University Medical Center
2004-2024
Washington University in St. Louis
2024
Cleveland Clinic
2024
Brigham and Women's Hospital
2024
Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location present aggregates HD cell culture models, transgenic mice, human postmortem brain. specifically interfere CBP-activated gene transcription, overexpression of...
Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration neurons in brain regions such as the hippocampus, resulting progressive cognitive dysfunction. The pathogenesis AD tightly linked to Aβ oxidative stress, but it remains unclear how these factors result neuronal dysfunction death. We report alterations sphingolipid cholesterol metabolism during normal aging brains patients that accumulation long-chain ceramides...
A fundamental challenge in the post-genome era is to understand and annotate consequences of genetic variation, particularly within context human tissues. We present a set integrated experiments that investigate effects common variability on DNA methylation mRNA expression four brain regions each from 150 individuals (600 samples total). find an abundance cis regulation show for first time abundant quantitative trait loci CpG across genome. peak enrichment QTLs be approximately 68,000 bp...
Endocytosis is critical to the function and fate of molecules important Alzheimer's disease (AD) etiology, including β protein precursor (βPP), amyloid (Aβ) peptide, apolipoprotein E (ApoE). Early endosomes, a major site Aβ peptide generation, are markedly enlarged within neurons in Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation specific very early response AD. To evaluate activation, used markers internalization (rab5, rabaptin...
Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important survival dopamine neurons Parkinson's disease (PD). We show parkin S-nitrosylated vitro, as well vivo a mouse model PD and brains patients with diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's activity its protective function. The inhibition by could contribute to degenerative process these disorders impairing substrates.
The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to large group unstable microsatellite diseases. Previously, we showed mutations can be bidirectionally transcribed these express unexpected proteins by unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, show C9ORF72 antisense transcripts are elevated brains...
Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across lifespan of 55 cognitively intact individuals aged 20-99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions forebrain exhibited substantially profile age. For example, comparing equally powered groups, 5,029 probe sets significantly altered age compared 1,110...
We tested the hypothesis that synaptic defects in hippocampus of individuals with Alzheimer disease (AD) correlate severity cognitive impairment. Three postmortem groups were studied: controls normal and stable cognition; cognitively intact subjects senile plaque densities diagnostic for possible AD (p-AD) neurofibrillary changes characteristic early (Braak stage III); definite typical incipient to severe III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels quantified by...
Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, limited understanding this RNA-binding protein (RBP) impedes the clarification pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing conserved exons, we found repressed nonconserved cryptic maintaining intron integrity. When was depleted from mouse embryonic stem...
Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and progression remains controversial. Analyses tau animal models suggest that phenotypes coincide with accumulation soluble aggregated species but not NFTs. The role prefilamentous aggregates, e.g., oligomeric intermediates, is poorly understood, in part because methodological challenges. Here, we engineered novel oligomer-specific antibody, T22, used it to...
Although ubiquitin-enriched protein inclusions represent an almost invariant feature of neurodegenerative diseases, the mechanism underlying their biogenesis remains unclear. In particular, whether topology ubiquitin linkages influences dynamics is not well explored. Here, we report that lysine 48 (K48)- and 63 (K63)-linked polyubiquitination, as monoubiquitin modification contribute to inclusions. K63-linked polyubiquitin most consistent enhancer formation. Under basal conditions, ectopic...
Abnormal biology of α-synuclein (α-Syn) is directly implicated in the pathogenesis Parkinson's disease and other α-synucleinopathies. Herein, we demonstrate that C-terminally truncated α-Syn (α-SynΔC), enriched pathological aggregates, normally generated from full-length independent aggregation brains cultured cells. The accumulation α-SynΔC enhanced neuronal cells as compared with nonneuronal Significantly, expression familial disease-linked mutant associated cellular α-SynΔC. Moreover,...
Abstract Introduction It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. Methods Within the autopsy cohort of Baltimore Longitudinal Study Aging, we measured concentration and assessed ratios glycolytic amino acids, serine, glycine, alanine to glucose. We also quantified protein levels neuronal (GLUT3) astrocytic (GLUT1) transporters. Finally, relationships between plasma before death tissue Results Higher...
Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism AD pathogenesis are unclear. Understanding how global perturbations related to severity neuropathology eventual expression symptoms at-risk individuals critical developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses both brain blood identify correlates their associations with prodromal...
PAR promotes α-synuclein toxicity How pathologic (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see Perspective by Brundin and Wyse). They found that α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) inhibition PARP or knockout PARP-1 protected mice from pathology. The generation PFF–induced activation converted PFF a strain was 25-fold...