A5017323656- Neuroinflammation and Neurodegeneration Mechanisms
- Cell death mechanisms and regulation
- Chronic Lymphocytic Leukemia Research
- Immune Response and Inflammation
- Autophagy in Disease and Therapy
- interferon and immune responses
- Amyotrophic Lateral Sclerosis Research
- Neuroscience and Neuropharmacology Research
- Chronic Myeloid Leukemia Treatments
- Alzheimer's disease research and treatments
- Mitochondrial Function and Pathology
- Phagocytosis and Immune Regulation
- Immune cells in cancer
- Trace Elements in Health
- Hereditary Neurological Disorders
- Ferroptosis and cancer prognosis
- Peripheral Neuropathies and Disorders
- Ubiquitin and proteasome pathways
- Multiple Sclerosis Research Studies
- NF-κB Signaling Pathways
- Inflammasome and immune disorders
- Endoplasmic Reticulum Stress and Disease
- Cardiac Ischemia and Reperfusion
- PI3K/AKT/mTOR signaling in cancer
- Caveolin-1 and cellular processes
Sanofi (United States)
2018-2025
Sanofi (France)
2024
Sanofi (Mexico)
2021-2024
AVEO Oncology (United States)
2023
Neurological Research Institute
2021
Framingham State University
2021
Harvard University
2012-2018
Biogen (United States)
2017-2018
Albert Einstein College of Medicine
2008-2012
John F. Kennedy Center for the Performing Arts
2008-2009
Mutations in the optineurin (OPTN) gene have been implicated both familial and sporadic amyotrophic lateral sclerosis (ALS). However, role of this protein central nervous system (CNS) how it may contribute to ALS pathology are unclear. Here, we found that actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss OPTN led progressive dysmyelination axonal degeneration through engagement necroptotic machinery CNS, including RIPK1, RIPK3,...
Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by loss oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), proinflammatory cytokine implicated in MS, can activate necroptosis, necrotic cell death pathway regulated RIPK1 RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well activation RIPK1, RIPK3, MLKL, hallmark mediators cortical lesions human MS pathological samples. Furthermore,...
Significance Dysfunction of microglia plays a fundamental role in the pathogenesis Alzheimer’s disease (AD), most common form dementia. However, there is lack knowledge about targets that can be safely manipulated for modulating treatment AD. The presence unique subtype disease-associated (DAM) has recently been implicated mediating mechanism promotes development DAM unclear, nor it known how may modulate progression This study demonstrates RIPK1-dependent transcription and lysosomal defects...
Abstract Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in of patients with COVID-19 elucidate potential mechanisms underlying the vascular pathology. In brains severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals animal models, found an increased number empty basement membrane tubes, so-called string representing remnants lost capillaries. We obtained evidence that brain...
Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found affected brain regions, but how iron accumulation influences physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived grown a tri-culture system highly responsive susceptible ferroptosis, an iron-dependent form of cell death. Furthermore, overload causes marked...
Missense mutations in the gene TP53 , which encodes p53, one of most important tumor suppressors, are common human cancers. Accumulated mutant p53 proteins known to actively contribute development and metastasis. Thus, promoting removal cancer cells may have therapeutic significance. Here we investigated mechanisms that govern turnover nonproliferating using a combination pharmacological genetic approaches. We show suppression macroautophagy by multiple means promotes degradation through...
Significance This study demonstrates a distinct mode of RIPK1 activation mediated by detergent-insoluble, highly ubiquitinated, activated species (iuRIPK1) which functions as critical intermediate between TNF-receptor-associated complex I and assembly the cytosolic caspase platform II in RIPK1-dependent apoptosis (RDA). By conducting systematic screen for RDA regulators, we reveal regulation iuRIPK1 Parkinson’s disease (PD)-associated LRRK2, E3 ubiquitin ligase c-Cbl, ALS-associated NEK1....
Abstract Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate inflammation in the liver. We aimed to investigate role of necroptosis mediating deleterious processes associated with cholestatic disease. Hallmarks were evaluated biopsies primary biliary cholangitis (PBC) patients wild-type RIP3-deficient (RIP3 −/− ) mice subjected common bile duct ligation (BDL). The functional link...
Abstract Microglia serve as the innate immune cells of central nervous system (CNS) by providing continuous surveillance CNS microenvironment and initiating defense mechanisms to protect tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming morphology, producing pro-inflammatory cytokines. These initially a beneficial role, but continued activation drives neuroinflammation neurodegeneration. Multiple sclerosis (MS) is chronic,...
Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and required for initiation maintenance of tumors. Here we show that metabolic stress triggered perturbation receptor tyrosine kinase FLT3 non–acute myeloid leukemia cells sensitizes cancer to autophagy inhibition leads excessive activation chaperone-mediated (CMA). Our data demonstrate an important sensor cellular nutritional state elucidate the role molecular mechanism CMA regulation...
The mammalian target of rapamycin (mTOR) is a key regulator cell growth, autophagy, translation, and survival. Dysregulation mTOR signaling associated with cancer, diabetes, autism. However, role for in neuronal death not well delineated. Here we show that global ischemia triggers transient increase phosphorylation at S2448, whereas decreasing p-mTOR functional activity selectively vulnerable hippocampal CA1 neurons. decrease coincides an biochemical markers pS317-ULK-1, pS14-Beclin-1,...
Receptor interacting protein kinase 1 (RIPK1) mediates cell death and inflammatory signaling is increased in multiple sclerosis (MS) brain samples. Here, we investigate the role of glial RIPK1 activity mediating MS pathogenesis. We demonstrate levels correlate with disease progression. find microglia are susceptible to RIPK1-mediated identify an gene signature that may contribute neuroinflammatory milieu patients. uncover a distinct for astrocytes regulating absence confirm...
Tolebrutinib is a covalent BTK inhibitor designed and selected for potency CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied translational approach evaluate three inhibitors Phase 3 clinical development MS with respect their relative block the METHODS: used vitro kinase cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) non-human primate cynomolgus estimate ability these candidates (evobrutinib, fenebrutinib,...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation prominent in ALS, but the cell state dynamics pathways driving remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords identified altered glial states, including increased expression inflammatory activation markers. Many these signals converged on inflammation death regulator receptor-interacting protein...
Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period enhanced permeability of mitochondrial membranes. The precise mechanisms by which function disrupted are, as yet, unclear. Here we show promotes alterations membrane contact points, rise intramitochondrial Zn<sup>2+</sup>, and activation large, multi-conductance channels outer membranes 1 h after insult. Mitochondrial channel activity was associated with protease...