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Identification of TDP-43 modifiers through single-cell transcriptional and epigenomic dissection of ALS and FTLD-MND

通过 ALS 和 FTLD-MND 的单细胞转录和表观基因组解剖鉴定 TDP-43 修饰物

基本信息

批准号：
10273669
负责人：
Veronique Belzil
金额：
$ 181.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-29 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273669
关键词：
ALS patients Address Affect Amyotrophic Lateral Sclerosis Astrocytes Autopsy Bayesian Method Biological Biological Models Brain Pathology C9ORF72 CRISPR screen Candidate Disease Gene Cell model Cells Characteristics Clinical Coculture Techniques Computational Technique DNA Data Data Set Deposition Development Diagnosis Disease Dissection Distal Dura Mater Enhancers Exclusion Exhibits Family Fibroblasts Frequencies Frontotemporal Lobar Degenerations Gene Expression Profile Gene-Modified Genes Genetic Genetic Risk Genetic Transcription Health Human Individual Induced pluripotent stem cell derived neurons Lead Light Link Liquid substance Maps Mediating Mediation Molecular Motor Motor Cortex Motor Neuron Disease Motor Neurons Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Nuclear Nucleic Acid Regulatory Sequences Pathogenesis Pathologic Pathology Pathway interactions Patients Phase Phase Transition Phenotype Physiological Population Prefrontal Cortex Protein Isoforms RNA RNA-Binding Proteins Recording of previous events Regulatory Element Research Resolution Resources Sampling Single Nucleotide Polymorphism Symptoms Therapeutic Therapeutic Intervention Thoracic spinal cord structure Tissues Transcription Alteration Validation Variant cell type clinical phenotype differential expression epigenomics experimental study familial amyotrophic lateral sclerosis frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic information genetic manipulation genome wide association study genome-wide genomic locus in vivo in vivo Model induced pluripotent stem cell insight mouse model neuron loss neuropathology neurotoxicity new therapeutic target novel pre-clinical predictive signature prevent protein TDP-43 risk variant single-cell RNA sequencing sporadic amyotrophic lateral sclerosis therapeutic target trait transcriptome

项目摘要

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative conditions with no current treatment to prevent, decelerate or stop neuronal death in patients. ALS and FTLD are clinically distinct but show an overlap in postmortem brain pathology and genetic factors: nuclear clearance and cytoplasmic accumulation of TDP-43 in affected central nervous system (CNS) regions is observed in 98% of ALS and 50% of FTLD patients. While initial symptoms lead to the diagnosis of either ALS or FTLD, up to 50% of ALS patients eventually develop symptoms of FTLD, with ~15% of patients ultimately receiving both diagnoses (FTLD with motor neuron disease, FTLD/MND). Mutations in the gene encoding TDP-43 (TARDBP) lead to rare cases of ALS, while TDP-43 pathology is observed in patients carrying more prevalent mutations, such as a pathological C9orf72 hexanucleotide repeat expansion (C9orf72+)—the most common genetic cause of ALS and FTLD identified thus far. TDP-43 therefore appears to be a pivotal and convergent factor in the pathogenesis of both ALS and FTLD. Despite this, however, the reasons for selective vulnerability of motor neurons, the mechanisms responsible for TDP-43 mislocalization, and the impact on neuronal health of nuclear TDP-43 exclusion and aberrant liquid-liquid phase separation underlying cytoplasmic demixing remain unknown. To address this challenge, in Aim 1, we systematically profile the transcriptional and epigenomic alterations of ALS and FTLD/MND patients at single-cell resolution using post-mortem CNS samples. In Aim 2, we integrate the resulting datasets to study the link between genetic, epigenomic, transcriptional, and cellular signatures of ALS and FTLD/MND. We associate these links with available clinical information, elucidate the genes and biological pathways altered in each, and predict new therapeutic targets. In Aim 3, we validate the molecular and cellular effects of these targets by assessing their impact on neuronal viability and TDP-43 functions/aggregation using high-throughput directed perturbation experiments. We study both cell-autonomous and non-cell-autonomous effects of these perturbations in human dura fibroblast-derived iPSC neurons and astroglia. In Aim 4, we perform neuropathological analyses of TDP-43 modifiers in ALS and FTLD/MND postmortem tissues, and endeavor to rescue in vivo pathology and phenotypes in a mouse model. The resulting datasets, analyses, and dura-derived iPSCs will provide an invaluable resource to understand the mechanisms of TDP-43 pathology in ALS and FTLD/MND, and may reveal putative therapeutic targets able to mitigate TDP-43 pathology through genetic manipulation.

摘要