A5067964335- Amyotrophic Lateral Sclerosis Research
- Biochemical Acid Research Studies
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Genetic Neurodegenerative Diseases
- Neurological diseases and metabolism
- Mitochondrial Function and Pathology
- Calcium signaling and nucleotide metabolism
- Neuroscience and Neuropharmacology Research
- Planarian Biology and Electrostimulation
- Cellular transport and secretion
- Muscle Physiology and Disorders
- Ion channel regulation and function
- Redox biology and oxidative stress
- Genomics, phytochemicals, and oxidative stress
- Adipose Tissue and Metabolism
- Cholinesterase and Neurodegenerative Diseases
- Endoplasmic Reticulum Stress and Disease
Weill Cornell Medicine
2017-2024
Cornell University
2017-2024
Tri-Institutional PhD Program in Chemical Biology
2024
MIND Research Institute
2017-2023
Brown University
2016
The objective of this study was to investigate cellular bioenergetics in primary skin fibroblasts derived from patients with amyotrophic lateral sclerosis (ALS) and determine if they can be used as classifiers for patient stratification. We assembled a collection unprecedented size sporadic ALS (sALS, n = 171), (PLS, 34), ALS/PLS C9orf72 mutations (n 13), healthy controls 91). In search novel classifiers, we performed extensive studies fibroblast bioenergetics, including mitochondrial...
Abstract Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, molecular mechanisms which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes models highly dependent on transgene dosage. Thus, issues whether these stem...
Abstract The endoplasmic reticulum (ER) is an important regulator of Ca 2+ in cells and dysregulation ER calcium homeostasis can lead to numerous pathologies. Understanding how various pharmacological genetic perturbations impacts cellular physiology would likely be facilitated by more quantitative measurements levels that allow easier comparisons across conditions. Here, we developed a ratiometric version our original ER-GCaMP probe allows for the concentration cell types sub-cellular...
Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, showed that mutant human SOD1 impairs oxidative phosphorylation, calcium homeostasis, dynamics. However, recent reports indicated alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead defects...
We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calcium regulation. Cells sense ER folding through H 2 O 2, which induces Nrf2 nuclear translocation. regulates expression GPx8, an glutathione peroxidase that modulates levels. Because is dependent on calcium, this as rheostat Protein misfolding dysregulation contribute to pathophysiology many diseases, including amyotrophic lateral sclerosis, in astrocytic participates...
Abstract Inhibitory neurons shape the brain’s computational landscape and rely on different cellular architectures intrinsic properties than excitatory neurons. Maintenance of overall balance (E) versus inhibitory (I) drive is essential, as disruptions can lead to neuropathological conditions, including autism epilepsy. Metabolic perturbations are a common driver E/I imbalance but differential sensitivity these two neuron types metabolic lesions not well understood. Here, we characterized...
Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts 43-controls, we found ~25% of sALS cases (termed sALS-1) transsulfuration pathway upregulation, where methionine-derived-homocysteine channeled into cysteine glutathione synthesis. sALS-1 fibroblasts selectively exhibited growth defect...
Abstract Sporadic amyotrophic lateral sclerosis (sALS) is a progressive motor neuron disease resulting in paralysis and death. Genes responsible for familial ALS have been identified, however the molecular basis sALS unknown. To discover metabotypic biomarkers that inform on etiology, untargeted metabolite profiling was performed 77 patient-derived dermal fibroblast lines 45 age/sex-matched controls. Surprisingly, 25% of showed upregulated methionine-derived homocysteine, channeled to...
Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease with limited therapeutic options. Biomarkers are needed for early detection, clinical trial design, and personalized medicine. Early evidence suggests that specific morphometric features in ALS primary skin fibroblasts may be used as biomarkers; however, this hypothesis has not been rigorously tested conclusively large fibroblast populations. Here, we imaged ALS-relevant organelles (mitochondria, ER, lysosomes)...
Abstract Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive paralysis and death. Most ALS cases are sporadic (sALS) patient heterogeneity poses formidable challenge for the development of viable biomarkers effective therapies. Applying untargeted metabolite profiling on 77 sALS patient-derived primary dermal fibroblast lines 45 sex/age matched controls, we found that ∼25% cell (termed sALS-1) upregulated trans-sulfuration, where methionine-derived homocysteine...
Abstract Objective Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease with limited therapeutic options. Diagnostic and surrogate endpoint biomarkers are needed for early detection, clinical trial design, personalized medicine. Methods We tested the predictive power of large set primary skin fibroblast (n=443) from sporadic familial ALS patients healthy controls. measured morphometric features endoplasmic reticulum, mitochondria, lysosomes by imaging vital dyes. also...