Exploring the Pathogenic Mechanisms of Batten's disease MFSD8 mutations using patient iPSC derived neurons.

使用患者 iPSC 衍生的神经元探索巴顿病 MFSD8 突变的致病机制。

基本信息

批准号：
10581666
负责人：
Joseph R Mazzulli
金额：
$ 20万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581666
关键词：
Adolescent Amino Acids Astrocytes Axon Biochemical Biological Assay Biological Markers Blindness Blood Brain CTSD gene Categories Cathepsins B Cell Death Cell Line Cells Ceroid Cessation of life Childhood Classification Coculture Techniques Data Dementia Dendrites Disease Disease Progression Event Fibroblasts Foundations Frontotemporal Dementia Functional disorder Genes Genetic Genetic Diseases Heterozygote Histopathology Hydrolase In Vitro Induced pluripotent stem cell derived neurons Inherited Lewy Body Dementia Link Lysosomal Storage Diseases Lysosomes Maintenance Mass Spectrum Analysis Membrane Proteins Modeling Mutation Nerve Degeneration Neurites Neurodegenerative Disorders Neuroglia Neurologic Dysfunctions Neurologic Symptoms Neuronal Ceroid-Lipofuscinosis Neurons PARK9 gene Parkinson Disease Pathogenicity Pathology Pathway interactions Patients Phenotype Point Mutation Population Predisposition Proteins Proteome Proteomics Role Seizures Solubility Spielmeyer-Vogt Disease Stable Isotope Labeling Structure Techniques Toxic effect Toxin Variant Western Blotting Work age related age related neurodegeneration alpha synuclein extracellular falls glucosylceramidase induced pluripotent stem cell infancy inhibitor insight link protein lipopigments loss of function loss of function mutation neuronal survival neurotoxicity new therapeutic target novel novel therapeutics personalized medicine pharmacologic premature presynaptic protein aggregation proteostasis solute synucleinopathy

项目摘要

Mutations in the MFSD8 gene cause CLN7 Batten’s disease (BD), a rare neurodegenerative lysosomal storage disorder characterized by the accumulation of a lipopigment called ceroid in the brain. Furthermore, MFSD8 mutations were recently associated with frontotemporal dementia (FTD), and other BD-associated genes are linked to Parkinson’s disease (ATP13A2) and other subtypes of FTD (GRN, CTSD). CLN7 BD falls within a broader category of pediatric diseases called neuronal ceroid lipofuscinoses (NCL) that share common histopathology of ceroid accumulation in neurons and neurological symptoms including dementia, blindness, seizures, and premature death. The MFSD8 gene encodes the CLN7 protein, a membrane protein of unknown function that is localized to lysosomes. Mutations that cause CLN7 BD are loss of function and many of the known mutations result in premature stops or point mutations that destabilize the protein. Our previous studies in patient fibroblasts demonstrated that loss of CLN7 reduces lysosomal hydrolase activity, autophagic flux, and the accumulation of autofluorescent material. While these studies contributed to our understanding of how CLN7 leads to disease, the mechanisms that lead to neurodegeneration are not known. Furthermore, there are no studies done in relevant patient-derived neuronal models. Here, we propose to explore the mechanisms of neurotoxicity caused by CLN7 mutations, using a several iPSC-lines derived from distinct BD patients. Our preliminary data indicates that CLN7 BD lines can develop into cortical neurons in vitro, but demonstrate lysosomal phenotypes and reduced neurite extensions. In aim 1, we plan to use this established neuronal model to determine how loss of CLN7 influences the stability of the proteome and protein solubility to discover novel pathways and generate hypotheses for how cell death occurs in CLN7 BD. In aim 2, we will assess rescue mechanisms that aim to restore protein homeostasis in CLN7 neurons, as well as co-culturing wild-type astrocytes with CLN7-BD neurons to assess the role of glia cells in dementia. Since almost no mechanistic information is known about how CLN7 causes neurological dysfunction, our studies have the potential to uncover novel therapeutic pathways for CLN7 BD and other NCLs that share similar pathologies. Beyond NCLs, mutations in MFSD8 are associated with FTD, an age-related neurodegenerative disorder, and therefore our studies may be relevant to more common age-related neurodegeneration. Since there is accumulating evidence for lysosomal dysfunction common sporadic diseases including Parkinson’s disease and other synucleinopathies, our studies may have a broad impact on the field.

MFSD8基因的突变引起CLN7 BATTEN疾病（BD），一种罕见的F脂肪在大脑中称为CEROID。小儿疾病称为神经元的脂肪肌蛋白酶（NCL），它们在神经元中共有共同的组织病理学，包括神经元中的神经症和神经系统症状，包括痴呆症，失明和过早死亡。功能和许多已知突变导致对患者成纤维细胞的先前研究表明，CLN7的损失降低了溶酶体的活性CLN7突变引起的神经毒性的机制，使用来自不同BD患者的几个IPSC线，表明我们的初步数据可以在体外发展成皮质神经元，但在AIM 1中表现出溶酶体表现出来。使用已建立的神经元模型来确定CLN7的损失如何影响蛋白质组AD蛋白溶解度的稳定性，以发现途径并为CLN7 BD中的细胞死亡产生假设。以及与CLN7-BD神经元共同培养的胶质细胞在痴呆症中的作用。病理学。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CLN7/MFSD8 may be an important factor for SARS-CoV-2 cell entry.

DOI：
10.1016/j.isci.2022.105082
发表时间：
2022-10-21
期刊：
ISCIENCE
影响因子：
5.8
作者：
Heinl, Elena -Sofia;Lorenz, Sebastian;Schmidt, Barbara;Laqtom, Nouf Nasser M.;Mazzulli, Joseph R.;Francelle, Laetitia;Yu, Timothy W.;Greenberg, Benjamin;Storch, Stephan;Tegtmeier, Ines;Othmen, Helga;Maurer, Katja;Steinfurth, Malin;Witzgall, Ralph;Milenkovic, Vladimir;Wetzel, Christian H.;Reichold, Markus
通讯作者：
Reichold, Markus