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Profiles of Common and Unique aspects of Upper Motor Neuron degeneration in HSP and ALS

HSP 和 ALS 上运动神经元变性的共同和独特方面的概况

基本信息

批准号：
10526893
负责人：
Pembe Hande Ozdinler
金额：
$ 44万
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：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526893
关键词：
ALS pathology ALS patients Actins Amyotrophic Lateral Sclerosis Attention Binding Proteins Biology Brain Cell physiology Characteristics Clinical Complex Defect Disease Event Experimental Designs Fluorescence Foundations Future Gene Expression Gene Expression Profile Genes Genetic Genotype Goals Hereditary Spastic Paraplegia Human Investigation Knowledge Label Modeling Molecular Molecular Genetics Motor Cortex Motor Neuron Disease Motor Neurons Movement Mus Mutate Mutation Nerve Degeneration Neurons Pathology Pathway interactions Patients Population Protein Dynamics Proteins Proteomics RNA Splicing Reporter Reverse Transcriptase Polymerase Chain Reaction Role Sampling Structure Therapeutic Therapeutic Intervention Time Transcript Tubulin UCHL1 gene Upper Motor Neuron Disease Variant Western Blotting cell type druggable target effective therapy immunocytochemistry insight interest internal control metabolomics motor neuron degeneration mouse model neuron loss neuropathology profilin protein TDP-43 spastin transcriptome sequencing treatment strategy

项目摘要

ABSTRACT/ PROJECT SUMMARY: The movement starts in the brain. Especially for motor neuron diseases, which impact voluntary movement, the brain component requires better understanding and assessment. Upper motor neurons (UMNs), located in layer 5 of the motor cortex, have a unique role for the initiation and modulation of voluntary movement. Their progressive degeneration is the characteristic hallmark of neuropathology observed in hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS) patients. In striking contrast to their clinical importance and relevance, very little is known about the underlying causes of their vulnerability and progressive loss. This lack of information and understanding of the cellular and genetic basis of their vulnerability, as well as the common and unique aspects of their neurodegeneration hinders our ability to develop effective and long-term treatment strategies for diseases of the UMN. In an effort to bring a mechanistic insight into the cellular and molecular basis of UMN degeneration in two distinct diseases, such as HSP and ALS, we are going to take advantage of the UCHL1-eGFP mice, a reporter line in which the UMNs are genetically labeled with fluorescence. In this proposal, we will focus our attention to the Profilin and Spastin, because like Spastin, Profilin is an actin/tubulin-binding protein, and mutations in profilin results in ALS, whereas mutations in spastin results in HSP. To date numerous mouse models are generated to mimic the human condition. We crossed the hPFN1G118V (generated by Dr. Kiaei) and SPASTC448Y mice (generated by Dr. Baas) with UCHL1-eGFP mice to generate the UMN reporter lines with these mutations. Since we have shown that the UMNs of ALS patients with TDP-43 pathology and mouse UMNs of TDP-43 model share the same aspects of neurodegeneration at a cellular level, we will focus our attention to the neurons and purify diseased UMNs from the complex structure of the brain as a “pure” neuron population at different stages of the disease to investigate the dynamic changes in their gene expression profile as well as the proteins that are present in them, with respect to the healthy UMNs. As an internal control, we will use UMNs isolated from TDP- 43 mouse model not only because TDP-43 pathology is widely observed in ALS and HSP, but also because this model better represents the spectrum of ALS. Upon completion, our results will begin to reveal the common and unique aspects of UMN vulnerability in HSP and ALS, it will also suggest the distinct set of genes and/or proteins that are responsible for the initiation of their vulnerability. Most importantly our results have the potential to identify druggable targets and pathways of interest for future therapeutic interventions.

摘要/项目概述：