A5064888571- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Alzheimer's disease research and treatments
- Genetic Neurodegenerative Diseases
- Neurological diseases and metabolism
- Parkinson's Disease Mechanisms and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA and protein synthesis mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Bioinformatics and Genomic Networks
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Congenital heart defects research
- Prion Diseases and Protein Misfolding
- Epigenetics and DNA Methylation
- Biochemical Acid Research Studies
- Single-cell and spatial transcriptomics
- Neuroscience and Neural Engineering
- Cellular transport and secretion
- Pluripotent Stem Cells Research
- Microtubule and mitosis dynamics
- Click Chemistry and Applications
- Viral Infections and Immunology Research
- Trace Elements in Health
Emory University
2015-2025
William Harvey Research Institute
2022
Queen Mary University of London
2022
Praxis (United States)
2022
Haukeland University Hospital
2022
King's College London
2022
University College London
2022
National Hospital for Neurology and Neurosurgery
2022
University of Bergen
2022
The Wallace H. Coulter Department of Biomedical Engineering
2015-2020
Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence TMEM106B rs3173615 protective genotype was associated longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting slower disease course. The seminal discovery filaments derived from is common feature aging and, across range neurodegenerative disorders,...
Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations the PGRN gene (GRN) are common cause of frontotemporal lobar degeneration (FTLD) lead to disease through haploinsufficiency. Additionally, complete loss humans leads ceroid lipofuscinosis (NCL), lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic features NCL. Further, GRN variants that decrease expression...
We performed a pilot screen to assess the utility of NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in identification amyotrophic lateral sclerosis (ALS) biomarkers. Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via multiplexed assay that includes 120 neurodegeneration-associated proteins. Statistical analysis results identify proteins differentially expressed plasma their correlation with...
Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to loss RNA-binding protein FMRP. In addition regulating mRNA translation and synthesis, emerging evidence suggests that FMRP acts coordinate proliferation differentiation during early neural development. However, whether FMRP-mediated translational control is related impaired cell fate specification developing human brain remains unknown. Here, we use patient induced pluripotent stem (iPSC)-derived progenitor cells...
Although β-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic tachycardia (CPVT), this treatment is unsuccessful ∼25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these have potential for use investigating the phenomenon, but it remains unknown whether they recapitulate patient-specific drug responses β-blockers. This study assessed inadequacy β-blocker therapy an individual...
A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). remarkably similar intronic TG3C2 associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, can undergo repeat-associated non-ATG (RAN) translation to dipeptide proteins (DPRs). Yet, these diseases result degeneration distinct subsets neurons. We show that expression mice sufficient...
Abstract The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks several neurodegenerative diseases provide a defining criterion for the neuropathologic diagnosis Limbic-predominant Age-related Encephalopathy (LATE). LATE changes (LATE-NC) often comorbid with other pathologies including Alzheimer’s disease (ADNC). We examined whether regulated cryptic exons accumulate in hippocampus neuropathologically confirmed LATE-NC cases. found that RNAs robustly...
Abstract Background Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years onset. Although roughly 10 % cases can be linked to specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause majority is unknown. Consequently, there critical need for biomarkers that reflect onset and progression across ALS subgroups. Methods We employed tandem mass tag spectrometry...
One of the defining pathological features Alzheimer's disease (AD) is deposition neurofibrillary tangles (NFTs) composed hyperphosphorylated tau in brain. Aberrant activation kinases AD has been suggested to enhance phosphorylation and toxicity tau, making responsible attractive therapeutic targets. The full complement tau-interacting brain their activity remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1)...
Repeat expansions in the C9orf72 gene are most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place dorsolateral frontal cortex patients with ALS/FTD, we compared healthy controls ALS/FTD donor samples staged based on levels cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark disease progression. We identified distinct changes different cell types during FTD...
Environmental influences and insults by reproductive toxicant exposure can lead to impaired spermatogenesis or infertility. Understanding how toxicants disrupt is critical for determining environmental factors contribute fertility. While current animal models are available, understanding of the toxic effects on human fertility requires a more robust model system. We recently demonstrated that pluripotent stem cells differentiate into spermatogonial cells/spermatogonia, primary secondary...
Cellular RNA labeling using light-up aptamers that bind to and activate fluorogenic molecules has gained interest in recent years as an alternative protein-based approaches. Aptamer-based systems are genetically encodable cover the entire visible spectrum. However, inherently temporary nature of noncovalent aptamer–fluorogen interaction limits utility these imaging does not withstand dye washout, dissociation can compromise tracking. We propose limitations be averted through covalent...
Abstract Background Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years onset. Although roughly 10% cases can be linked to specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) most are unknown. Consequently, there is critical need for biomarkers that reflect onset and progression across ALS subgroups. Methods We employed tandem mass tag spectrometry...
Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease Menkes are neurodevelopmental disorders resulting from mutations the transporters ATP7A ATP7B, with also causing occipital horn syndrome, distal neuropathy. A 65 year old male presenting brachial amyotrophic diplegia diagnosed lateral sclerosis (ALS) was found to harbor p.Met1311Val (M1311V) substitution variant ATP7A. ALS is fatal neurodegenerative associated progressive muscle weakness,...
The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but effects of this variant on neurodevelopment are not well understood. We interrogated developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from 3q29Del mouse model. profiled transcriptomes that were aged 2 12 months, as perinatal isocortex, all single-cell resolution. Systematic...
Abstract Repeat expansions in the C9orf72 gene are most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place dorsolateral frontal cortex patients with ALS/FTD, we compared healthy controls ALS/FTD donor samples staged based on levels cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark disease progression. We identified distinct changes different cell types during...
Abstract Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but complete cure has not been developed and related genes have defined in more than 80% of cases. Here we compared whole genome sequencing results from male ALS patient his healthy parents to identify relevant variants, chose one variant the X-linked ATP7A gene, M1311V, as strong disease-linked candidate after profound examination. Although this rare Ashkenazi Jewish population according aggregation...
Abstract Mutations in the human kinesin family member 5A ( KIF5A ) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several ALS variants exon 27 skipping and produce motor proteins with an altered C-terminal tail (referred to ΔExon27). However, underlying pathogenic mechanism is still unknown. In this study, we performed comprehensive analysis ΔExon27 at single-molecule, cellular, organism levels. Our results show that prone form cytoplasmic aggregates...
Fused in sarcoma (FUS) is a RNA/DNA protein involved multiple nuclear and cytoplasmic functions including transcription, splicing, mRNA trafficking, stress granule formation. To accomplish these many functions, FUS must shuttle between cellular compartments highly regulated manner. When shuttling disrupted, abnormally accumulates into inclusions that can be toxic. Disrupted of the nucleus hallmark ~10% frontotemporal lobar degeneration (FTLD) cases, neuropathology underlies dementia (FTD)....