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Cell-type-specific contributions to cortical dysfunction in frontotemporal dementia

细胞类型特异性对额颞叶痴呆皮质功能障碍的影响

基本信息

批准号：
10317335
负责人：
Rita Marie Cowell
金额：
$ 47.68万
依托单位：
SOUTHERN RESEARCH INSTITUTE
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：
2021-07-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317335
关键词：
Affect Affinity Chromatography Age Alzheimer&apos s disease related dementia Binding Bioinformatics Biological Assay Brain Buffers C9ORF72 Calcium Cell Culture Techniques Cell Death Cell physiology Cells Complex Computer Assisted Data Data Set Databases Defect Dementia Disease Progression Electrophysiology (science)Equilibrium Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Future Gene Expression Gene Expression Profile Gene Proteins Genes Genetic Transcription Glutamates Human Impairment Interneurons Intervention Knock-in Knock-in Mouse Lewy Body Dementia Mediating Modeling Motor Cortex Mus Mutation Nerve Degeneration Neurons Nuclear Parvalbumins Pathologic Pathology Pathway interactions Patients Pharmacology Population Prefrontal Cortex Property Protocols documentation RNA RNA Binding RNA Recognition Motif RNA Splicing RNA metabolism Reporting Resolution Ribosomes Somatostatin Source Spliced Genes TDP-43 aggregation Tissue-Specific Gene Expression Transcript Translating Work age related behavioral impairment cell type differential expression excitatory neuron experimental study gain of function gamma-Aminobutyric Acid hippocampal pyramidal neuron imaging study in vivo induced pluripotent stem cell inhibitory neuron loss of function mouse model mutant neurotransmission novel overexpression patch clamp prevent protein TDP-43 protein protein interaction

项目摘要

Frontotemporal dementia (FTD) is a debilitating, age-related neurodegenerative condition caused by frontotemporal lobar degeneration (FTLD), most often accompanied by the accumulation and/or dysfunction of the protein TDP-43 (FTLD-TDP). Aggregation of TDP-43, encoded by the TARDBP gene, occurs with or without concomitant mutations in TARDBP, suggesting that its accumulation represents a convergent mechanism underlying cortical vulnerability in FTD. The mechanisms underlying the detrimental effects of TDP-43 dysfunction are complex and likely involve both gain- and loss-of-function mechanisms, due to alterations in the intracellular compartmentalization and aggregation properties of TDP-43. Despite the availability of cell culture and mouse models of TDP-43 pathology, the precise mechanisms by which TARDBP mutations give rise to cortical dysfunction and cell loss in vivo are not clear. Recent imaging studies implicate a disruption in excitatory and inhibitory (E:I) balance in the cortex of patients with FTD, yet very little work has been done to explore the mechanisms by which this arises in vivo. Recent data generated using knockin and overexpression models of TDP-43 have revealed alterations in gene expression, function, and viability of cortical parvalbumin-expressing fast-spiking interneurons (PV-INs), cells which provide the main source of feed-forward GABAergic neurotransmission in the cortex and are critical for maintaining E:I balance. However, very little is known about the mechanisms underlying PV-IN vulnerability with Tardbp mutations in vivo and how PV-IN dysfunction contributes to pyramidal excitatory neuron function and loss. The experiments proposed in this application aim to identify the effects of TDP-43 mutation on PV-INs by assessing the PV-IN-specific transcriptional changes which occur during the progression of disease in Tardbp mutant knockin mice (Aim 1) and determining the impact of Tardbp mutations on PV-IN properties and cortical E:I balance with age (Aim 2). Differential gene expression and splicing profiles will be generated for PV-INs and compared to other neuron types using cell-type-specific translating ribosome purification protocols, with comparison to publicly available datasets of transcriptional changes in mouse and iPSC models of FTLD-TDP and other FTDs and TDP-43 RNA-binding assay databases. Computer-assisted modeling will be used to generate cell-type-specific protein-protein-interaction networks to identify convergent genes/proteins which could serve as targets for preventing cellular dysfunction. Electrophysiological approaches will explore the contributions of different cell types to the progression of cortical dysfunction, with comparison to a TDP-43 overexpression model to explore whether altered neuronal properties reflect a gain-of-function mechanism. These studies have the potential to reveal the mechanisms by which TDP-43 abnormalities influence cortical function and identify novel genes and/or pathways for promoting normal cortical function in patients with FTD.