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Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

基本信息

批准号：
10752966
负责人：
Rong Grace Zhai
金额：
$ 112.85万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752966
关键词：
Acetylation Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid Autophagocytosis Biochemical Biological Models Brain Brain Injuries Cells Chemicals Collaborations Data Set Doctor of Philosophy Drosophila genus Enzymes Family Female Fibroblasts Functional disorder Gene Expression Gene Expression Profiling Genetic Goals Grant Heterozygote Human Intervention Ischemic Brain Injury Legal patent Life Link Lysosomes Manuscripts Maps Mediating Metabolic Metabolic Diseases Metabolism Modeling Molecular Mutation Nerve Degeneration Nervous System Neurons Online Mendelian Inheritance In Man Outcome Oxidation-Reduction Pathogenesis Pathologic Pathology Pathway interactions Patients Phenylbutyrates Polyamine Catabolism Polyamines Protein Acetylation Putrescine Research Resistance Risk Factors Role School Nursing Snyder-Robinson syndrome Spermidine Spermine Spermine Synthase Tauopathies Testing Therapeutic Toxic effect Traumatic Brain Injury Universities Work X-linked intellectual disability biobank causal variant design in vivo in vivo Model loss of function lymphoblast male medical schools metabolic profile nervous system disorder neurodegenerative phenotype neuroprotection neurotoxicity novel pharmacologic polycation protein expression proteostasis tau Proteins tau aggregation tau mutation tissue culture transcriptome sequencing

项目摘要

Title: Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance PI: R. Grace Zhai, PhD, University of Miami School of Medicine, Miami, FL Co-I: Rich Steet, PhD, Greenwood Genetic Center, Greenwood, SC Co-I: Luigi Boccuto, MD, Clemson University School of Nursing, Clemson, SC PROJECT SUMMARY Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated polycations essential for life. First indications linking polyamine metabolism and neurological disorders came from the observations of abnormal polyamine levels accompanying several brain injury conditions including ischemic brain damage and traumatic brain injury. The pivotal role of polyamine metabolism emerged with the mapping of causal mutation of Snyder-Robinson Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes the conversion of spermidine to spermine. Our work in the previous grant cycle (R01 NS109640) investigated the pathological consequence of polyamine imbalance in the nervous system in the context of SRS. We have established a Drosophila model for SRS to recapitulate several key features of SRS pathology, have uncovered altered redox state, dysregulated protein acetylation, and lysosomal dysfunction as primary neurotoxicity underlying SRS pathology, and most importantly, have identified phenylbutyrate (PBA) as a robust pharmacological suppressor of neurotoxicity in SRS in vivo models and in patient cells. Recently, we made the exciting discovery of the critical connection between polyamine metabolism and Tau aggregation-induced neurodegeneration. Specifically, we found that while complete loss of SMS causes SRS, partial loss of SMS (SMS+/-, carriers) showed resistance to Tau-induced neurodegeneration in Tauopathy models. This finding has two important implications: first, polyamines may regulate Tau aggregational toxicity; and second, progression of neurodegeneration in Tauopathy could be delayed by modulating polyamine metabolism. Our objectives for this renewal application are to establish the mechanistic link between polyamine metabolism and Tau/amyloid aggregational neurotoxicity, and identify neuroprotective strategies based on modulating polyamine metabolism using complementary model systems; 1) in vivo Drosophila models, 2) human fibroblasts cells from SRS patients (male, SMS-/y) and heterozygous carriers (female, SMS+/-), and 3) gene expression analyses of human Alzheimer’s Disease related dementia (ADRD) datasets. We hypothesize that modulating polyamine metabolism and shifting spermine/spermidine ratio enhances autophagic flux, regulates global acetylation landscape, facilitates the clearance of toxic Tau/amyloid oligomer species, and confers resistance to neurodegeneration in proteinopathy. We propose to define metabolic and cellular mechanisms underlying SMS+/- mediated neuroprotection against Tau/amyloid accumulation-induced neurodegeneration in vivo in Drosophila (Aim 1); characterize autophagic flux and proteostasis in human primary cells of SRS patient (male, SMS-/y), carriers (female, SMS-/+), and controls (+/+) (Aim 2); and carry out analysis of ADRD RNAseq and protein expression datasets to identify polyamine dysregulation risk factors and metabolic targets for neuroprotection against ADRD (Aim 3). The proposed research will reveal novel chemical and molecular connection between polyamine metabolism and global protein homeostasis, and more importantly reveal a previously unexplored therapeutic direction for AD pathogenesis.

题目：精胺合酶缺乏和多胺失衡的神经毒性