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TBCK Encephaloneuronopathy: establishing the role of mitochondrial dysfunction in promoting neurodegeneration

TBCK 脑神经病：确定线粒体功能障碍在促进神经退行性变中的作用

基本信息

批准号：
10641750
负责人：
XILMA R ORTIZ-GONZALEZ
金额：
$ 19.56万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641750
关键词：
Address Affect Age Alleles Atrophic Autism Diagnosis Automobile Driving Autophagocytosis Biogenesis Biological Biological Assay Biology Brain Branched-Chain Amino Acids CRISPR/Cas technology Child Childhood Clinical Co-Immunoprecipitations Complex Data Disease Disease model Down-Regulation Encephalopathies Environment Epilepsy FRAP1 gene Face Fibroblasts Fishes Frameshift Mutation Frequencies Functional disorder Future Genes Genetic Diseases Genotype Glycoprotein Degradation Pathway Goals Homidium Bromide Human Impairment In Situ Independent Scientist Award Induced pluripotent stem cell derived neurons Institution Intellectual functioning disability Label Learning Leucine Measures Mitochondria Mitochondrial DNA Modeling Motor Neurons Mutation NADH Names Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurologic Symptoms Neurons Neurosciences Pathway interactions Patients Phenotype Phosphotransferases Physicians Physiological Play Positioning Attribute Protein Glycosylation Protein Kinase Proteomics Puerto Rican Quality Control Reporting Research Respiration Respiratory Chain Role Scientist Seizures Severities Signal Transduction Spinal Muscular Atrophy Symptoms Syndrome Techniques Testing Therapeutic Training Treatment Efficacy Work Zebrafish autistic autosome clinical diagnosis experimental study fluorescence lifetime imaging gene replacement in vivo insight loss of function mitochondrial dysfunction nervous system disorder neurodegenerative phenotype neurogenetics neuromuscular new therapeutic target novel novel therapeutics null mutation overexpression programs protein expression protein protein interaction tool vector

项目摘要

PROJECT SUMMARY Autosomal recessive mutations in the TBCK gene cause intellectual disability of variable severity. I have further characterized the neurologic phenotype of Puerto Rican children with a homozygous null mutation (p.R126X) in TBCK, which we designated the Boricua mutation. The biological mechanism underlying the genotype-phenotype correlations remain unclear. On one extreme, patients with the severe Boricua mutation develop progressive brain, cerebellar and motor neuron atrophy, coarse facial features and epilepsy. We named this severe syndrome TBCK-encephaloneuronopathy (TBCKE). On the other hand, other patients with biallelic TBCK mutations have clinical diagnosis of autism and/or intellectual disability, without evidence of neurodegeneration. The function of TBCK protein is unknown, but previous studies have shown absence of TBCK leads to downregulation of mTORC1 signaling. The mTORC1 pathway regulates autophagy, including the targeted degradation of mitochondria (mitophagy). I recently reported increased autophagic flux and impaired glycoprotein degradation in TBCKE patients’ fibroblasts, which was rescued by activating mTORC1 signaling with L-leucine. Our fibroblasts studies suggests that TBCKE patients have mitochondrial dysfunction and mitochondrial DNA (mtDNA) depletion. Furthermore, the degree of mtDNA depletion predicts the neurologic severity of TBCK disease. Therefore, I hypothesize that loss of function of TBCK in human neurons leads to mtDNA depletion and mitochondrial dysfunction due to excessive autophagic clearance of mitochondria. To test this hypothesis in more disease relevant models, I propose to generate TBCK-null induced pluripotent stem cell (iPSC) derived neurons (iNeu) and tbck-/- zebrafish. The goal of this proposal is to address whether loss of function of TBCK affects mitochondrial function in human neurons, and to determine whether mtDNA depletion modulates the severity of neurodegeneration in TBCK disease. Using novel disease models and unique tools to assay mitochondrial function, I propose to address the following questions: (Aim 1) Do human neurons lacking TBCK protein have excessive mitophagy? (Aim2) What is the function of TBCK? Can we define its protein-protein interactions in neurons? (Aim 3) Can TBCK- null zebrafish model the variable severity of TBCK disease? Can mtDNA depletion modulate the severity of the phenotype in vivo? The experiments outlined in this proposal will determine the role of mitochondria in TBCKE and whether mtDNA depletion is sufficient to drive the neurodegenerative phenotype or merely an epiphenomenon. This work will also provide training in novel techniques for assaying neuronal mitochondrial function in disease models in situ. I will also learn to develop and characterize zebrafish models of neurodevelopmental disease. Support from this K02 award will be instrumental in growing my independent research program as a physician scientist in a superb institutional environment towards my long-term goal of studying the role of mitochondrial dysfunction in pediatric neurodegenerative disorders.

项目总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.

DOI：
10.1093/braincomms/fcab215
发表时间：
2021
期刊：
Brain communications
影响因子：
4.8
作者：
Tintos-Hernández JA;Santana A;Keller KN;Ortiz-González XR
通讯作者：
Ortiz-González XR

Mitochondrial Dysfunction: A Common Denominator in Neurodevelopmental Disorders?

DOI：
10.1159/000517870
发表时间：
2021
期刊：
Developmental neuroscience
影响因子：
2.9
作者：
Ortiz-González XR
通讯作者：
Ortiz-González XR

Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.

DOI：
10.1016/j.xhgg.2023.100236
发表时间：
2023-10-12
期刊：
HUMAN GENETICS AND GENOMICS ADVANCES
影响因子：
0
作者：
Shieh, Joseph T.;Tintos-Hernandez, Jesus A.;Murali, Chaya N.;Penon-Portmann, Monica;Flores-Mendez, Marco;Santana, Adrian;Bulos, Joshua A.;Du, Kang;Dupuis, Lucie;Damseh, Nadirah;Mendoza-Londono, Roberto;Berera, Camilla;Lee, Julieann C.;Phillips, Joanna J.;Alves, Cesar A. P. F.;Dmochowski, Ivan J.;Ortiz-Gonzalez, Xilma R.
通讯作者：
Ortiz-Gonzalez, Xilma R.