Mechanism of STING-mediated Neuropathology in Niemann-Pick Disease

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Nan  Yan
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $467,088
Funding agency: National Institute of Neurological Disorders and Stroke

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disease caused by genetic mutations in the
NPC1 (95%) and NPC2 (5%) genes. Neurological features of NPC bear striking resemblances with Alzheimer’s
disease (AD), leading to some experts considering NPC as “Childhood Alzheimer’s”. No FDA-approved therapy
is available. Lipids and cholesterol defects associated with the NPC disease are well understood. However,
immune pathways underlying neuroinflammation and Purkinje cell death in the NPC disease remain unknown.
We recently found that the innate immune STING pathway is activated by NPC-deficiency, and genetic deletions
of STING pathway components in mice are able to remarkably rescue NPC neuropathology. The overall goal of
this project is to understand how STING drives neuropathology associated with the NPC disease. Aim 1 will
focus on intracellular mechanisms, where we will dissect how STING signaling is activated by NPC-deficiency.
Aim 2 will focus on brain tissue pathology, where we will comprehensively determine STING expression cell
types, activities and their functional contribution to the NPC disease. Aim 3 will focus on therapeutic assessment,
where we will treat Npc1-/- mice and NPC1 patient iPSC-derived cells with existing and new STING pathway
inhibitors. STING has been implicated in several neurodegenerative diseases including Parkinson’s disease,
ALS/FTD and now NPC1. Studies proposed here will provide a much-needed comprehensive understanding of
STING pathway function in the brain as well as a step-by-step mechanism from STING activation to
neuropathology.

Terms: <AD dementia><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Basal Transcription Factor><Basal transcription factor genes><Biology><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Death><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Survival><Cell Viability><Cells><Cerebellum><Cessation of life><Childhood><Cholesterol><Clinical><Cre-Lox><Cre-LoxP><Cre/LoxP><Cyclic GMP><Cycloamylose><Cyclodextrins><Cyclomaltooligosaccharides><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Defect><Degenerative Neurologic Disorders><Deoxyribonucleic Acid><Disease><Disorder><Encephalon><Endoplasmic Reticulum><Enlarged Liver><Enlarged Spleen><Ergastoplasm><FDA approved><FTD/ALS><FTLD/ALS><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Future><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic mutation><Goals><Golgi><Golgi Apparatus><Golgi Complex><Guanosine Cyclic Monophosphate><Hepatomegaly><Hortega cell><IFN><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immunes><Innate Immunity><Integral Membrane Protein><Interferon Regulatory Factor 3><Interferons><Intracellular Communication and Signaling><Intrinsic Membrane Protein><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Label><Ligands><Lipids><Lysosomes><Mediating><Mice><Mice Mammals><Microglia><Modeling><Murine><Mus><NPC1><NPC1 gene><Native Immunity><Natural Immunity><Neimann-Pick's Disease Type C><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological><Neurological Disorders><Neuronal Cholesterol Lipidosis><Niemann Pick C Disease><Niemann-Pick Diseases><Niemann-Pick Type C><Niemann-Pick's Disease Type C><Non-Specific Immunity><Nonspecific Immunity><Null Mouse><Paralysis Agitans><Parkinson><Parkinson Disease><Pathology><Pathway interactions><Pick Disease Type C><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Proteins><Proteomics><Publishing><Purkinje Cells><Purkinje's Corpuscles><Research><Sequence Alteration><Signal Transduction><Signal Transduction Systems><Signaling><Splenomegaly><Testing><Therapeutic><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Transmembrane Protein><Transmembrane Protein Gene><Wild Type Mouse><adapter protein><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><antagonism><antagonist><biological signal transduction><brain tissue><cGMP><cell sorting><cell type><cerebellar Purkinje cell><cofactor><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia amyotrophic lateral sclerosis><genomic alteration><gitter cell><iPS><iPSC><iPSCs><improved motor function><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inhibitor><innate immune pathways><innovate><innovation><innovative><lipoid histiocytosis (classical phosphatide)><mesoglia><microbial><microglial cell><microgliocyte><motor function improvement><necrocytosis><nerve cell death><nerve cell loss><neural inflammation><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological disease><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic><neuropathological><neuropathology><pathway><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pediatric><perivascular glial cell><prevent><preventing><primary degenerative dementia><progressive neurodegeneration><scRNA-seq><senile dementia of the Alzheimer type><sensor><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sphingomyelin lipidosis><sphingomyelinase deficiency><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trafficking><transcription factor><wildtype mouse>