A5021244706- Amyotrophic Lateral Sclerosis Research
- Mitochondrial Function and Pathology
- Parkinson's Disease Mechanisms and Treatments
- Neurogenetic and Muscular Disorders Research
- Neurological diseases and metabolism
- Genetic Neurodegenerative Diseases
- Biochemical Acid Research Studies
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- Nerve injury and regeneration
- Nuclear Receptors and Signaling
- Alzheimer's disease research and treatments
- Diet and metabolism studies
- Neurological disorders and treatments
- Histone Deacetylase Inhibitors Research
- Endoplasmic Reticulum Stress and Disease
- Prion Diseases and Protein Misfolding
- Adipose Tissue and Metabolism
- Cancer, Hypoxia, and Metabolism
- Cholinesterase and Neurodegenerative Diseases
- Neurogenesis and neuroplasticity mechanisms
- Redox biology and oxidative stress
- biodegradable polymer synthesis and properties
- Enzyme Structure and Function
- Heat shock proteins research
Cornell University
2016-2025
Weill Cornell Medicine
2017-2025
MIND Research Institute
2014-2024
New York Proton Center
2011
Burke Medical Research Institute
2004-2005
Massachusetts General Hospital
2001-2002
Harvard University
2000
Abstract TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated colocalize α‐synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat proteins are family chaperones that both constitutively expressed and induced by stressors, serve essential functions for refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone bodies. In addition, using cellular model aggregation, torsinA...
Cu, Zn superoxide dismutase (SOD1) has been detected within spinal cord mitochondria of mutant SOD1 transgenic mice, a model familial ALS. The copper chaperone for (CCS) provides with copper, facilitates the conversion immature apo-SOD1 to mature holoform, and influences in yeast cytosolic/mitochondrial partitioning SOD1. To determine how CCS affects G93A-SOD1-induced disease, we generated mice overexpressing crossed them G93A-SOD1 or wild-type mice. Both CCS/wild-type-SOD1 dual are...
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by motor neuron degeneration. Mutations in Cu,Zn-superoxide dismutase (SOD1) are responsible for 20% of familial ALS cases via toxic gain function. In mutant SOD1 transgenic mice, mitochondria spinal neurons develop abnormal morphology, bioenergetic defects and degeneration, which presumably implicated disease pathogenesis. mostly cytosolic protein, but substantial portion associated with organelles, including...
The antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) is predominantly localized in the cytosol, but it also found mitochondria. Studies yeast suggest that apoSOD1 imported into mitochondria and trapped inside by folding maturation, which facilitated its copper chaperone for SOD1 (CCS). Here, we show mammalian cells, mitochondrial localization dictated state, modulated several interconnected factors. First, intracellular distribution of CCS determines partitioning cytosol mitochondria:...
Motor neurons are progressively and predominantly degenerated in ALS, which is not only induced by multiple intrinsic pathways but also significantly influenced the neighboring glial cells. In particular, astrocytes derived from SOD1 mutant mouse model of ALS or human familial sporadic patient brain tissue directly induce motor neuron death culture; however, mechanisms pathological astroglial secretion remain unclear. Here we investigated abnormal calcium homeostasis altered exocytosis...
Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology its interactome, as well the effects of depletion or expression disease-associated mutations wild-type cells. We find that associates with membranes intermembrane space, where it interacts closely related protein, CHCHD2....
Research Article20 August 2018Open Access Source DataTransparent process Parkin is a disease modifier in the mutant SOD1 mouse model of ALS Gloria M Palomo Feil Family Brain and Mind Institute, Weill Cornell Medicine, New York, NY, USA Search for more papers by this author Veronica Granatiero Hibiki Kawamata Csaba Konrad Michelle Kim Andrea J Arreguin Dazhi Zhao Teresa A Milner Harold Margaret Milliken Hatch Laboratory Neuroendocrinology, The Rockefeller University, Giovanni Manfredi...
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...
A decline in α-ketoglutarate dehydrogenase complex (KGDHC) activity has been associated with neurodegeneration. Provision of succinyl-CoA by KGDHC is essential for generation matrix ATP (or GTP) substrate-level phosphorylation catalyzed ligase. Here, we demonstrate consumption respiration-impaired isolated and situ neuronal somal mitochondria from transgenic mice a deficiency either dihydrolipoyl succinyltransferase (DLST) or (DLD) that exhibit 20–48% decrease activity. Import into the...
The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)
Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated autosomal dominant diseases. Chchd10 knock-in mice harboring heterozygous S55L mutation (equivalent to human pathogenic S59L) develop fatal cardiomyopathy caused by CHCHD10 aggregation and proteotoxic integrated stress response (mtISR). In mutant hearts, mtISR is accompanied metabolic rewiring characterized increased reliance on glycolysis rather than fatty acid oxidation. To counteract this rewiring, were...
Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms ALS (fALS) account for approximately 10% cases and are associated with mutations in numerous genes. Alterations mitochondrial functions have been proposed contribute pathogenesis. Here, we employed direct conversion (DC) technique generate induced neurons (iMN) from skin fibroblasts investigate phenotypes patient-derived relevant cell...
Energy metabolism could influence amyotrophic lateral sclerosis (ALS) and progressive (PLS) pathogenesis the response to therapy. We developed a novel assay simultaneously assess mitochondrial content membrane potential in patients' skin fibroblasts. In ALS PLS fibroblasts, was increased decreased, relative healthy controls. higher correlated with age at diagnosis, it disease severity. These unprecedented findings fibroblasts shed new light onto help developing biomarkers predict evolution...
ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While neurons are affected cells in ALS, studies on pathophysiology of disease have highlighted importance non-cell autonomous mechanisms, which implicate astrocytes other glial cells. In subsets reactive lose their physiological functions become toxic for neurons, thereby contributing to pathogenesis. Evidence astrocyte contribution pathogenesis well established...
Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, biogenesis, and proteostasis. In humans, mutations in CHCHD10, protein unknown function, were recently associated dominant multi-system whose pathogenic mechanisms remain to be elucidated. Here, CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic...
Abstract Objective ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there great unmet therapeutic need. AMX0035, combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early clinical trials, but its mechanisms action remain to be elucidated. Therefore, our goal was obtain an unbiased landscape the molecular effects AMX0035 patient‐derived cells. Methods We investigated transcriptomic metabolomic...