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Using mitochondrial Ca2+ uptake as a therapeutic target for ALS

使用线粒体 Ca2 摄取作为 ALS 的治疗靶点

基本信息

批准号：
10659923
负责人：
Lan Wei-LaPierre
金额：
$ 48万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659923
关键词：
ALS pathology ALS patients Adult Alleles Amyotrophic Lateral Sclerosis Animals Attenuated Axon Bioenergetics Brain Buffers C9ORF72 Cell Death Cell Membrane Permeability Cuprozinc Superoxide Dismutase DNA-Binding Proteins Defect Degenerative Disorder Disease Disease Progression Dissection Distal Dominant-Negative Mutation Electron Microscopy Event Exercise Generations Genes Genetic Genetic Models Homeostasis Immunohistochemistry In Situ Longevity Measurement Membrane Potentials Mitochondria Molecular Motor Motor Neurons Mus Muscle Muscle Contraction Muscle Fibers Muscle denervation procedure Muscle function Mutation Neurodegenerative Disorders Neuromuscular Junction Onset of illness Outcome Paralysed Pathogenesis Pathologic Pathology Patients Performance Phenotype Property Reporting Research Respiratory Chain Respiratory Failure Role Signal Transduction Skeletal Muscle Soleus Muscle Spinal Cord Structure Symptoms System Testing Therapeutic Effect Tissues Transgenic Mice Treatment Efficacy Western Blotting amyotrophic lateral sclerosis therapy attenuation axonopathy behavioral study effective therapy extensor digitorum improved in vivo mitochondrial dysfunction mitochondrial membrane mouse model muscular structure neuron loss neuronal survival new therapeutic target postsynaptic pre-clinical preservation presynaptic prevent therapeutic target uptake

项目摘要

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation, and eventually, paralysis. Currently, no effective treatments are available to stop or reverse ALS disease progression and the precise molecular mechanisms underlie ALS pathogenesis remain elusive. Prior studies revealed decreased mitochondrial respiratory chain activity, altered mitochondrial ultrastructure, and mitochondrial dysfunction in both MN and skeletal muscle (SM) in ALS patients and mouse models. The first sign of ALS pathology occurs at the neuromuscular junction (NMJ), where presynaptic MN axons connect with postsynaptic SM end plates. To date, whether signals resulting in the initial NMJ damage are from MN or SM remain unclear. In this project, we aim to determine the tissue-specific causative role of mitochondrial Ca2+ uptake in SM and MN in disease onset and progression, and the therapeutic efficacy of reducing mitochondrial Ca2+ uptake on NMJ and SM function in ALS mice. We hypothesize that mitochondrial Ca2+ mishandling in both SM and MN actively contribute to ALS disease pathogenesis and that attenuating mitochondrial Ca2+ uptake mitigates mitochondrial damage and preserves NMJ/muscle function. To test this hypothesis, we will use transgenic mice with inducible, SM or MN-specific expression of a dominant negative form of the mitochondrial Ca2+ uniporter to specifically and selectively reduce mitochondrial Ca2+ uptake in SM and MN in hSOD1G93A mice and C9-500 (C9orf72) mice, two mouse models associated with the most prevalent genetic causes for ALS. The central hypothesis will be tested in two Specific Aims. Aim 1 will determine the role of mitochondrial Ca2+ uptake in SM or MN in survival, motor function, NMJ function and in vivo muscle performance in hSOD1G93A and C9-500 mice. Aim 2 will assess the impact of tissue-specific inhibition of mitochondrial Ca2+ uptake in SM or MN on NMJ and muscle structure, MN survival, muscle intrinsic contractile properties, mitochondrial structure and mitochondrial bioenergetics in SM of hSOD1G93A and C9-500 mice. This project will: 1) provide a systematic, longitudinal characterization of SM and NMJ function from a cellular level to whole animal level at different stages of disease progression in hSOD1G93A and C9-500 mice; 2) determine the degrees to which defects in mitochondrial Ca2+ uptake in SM or MN contribute to altered NMJ structure/function, disease onset and progression in hSOD1G93A and C9-500 mice; 3) provide the first detailed dissection on the relative role of mitochondrial Ca2+ uptake in SM and MN in ALS phenotype using the same genetic models and determine the origin of the signals that result in NMJ destruction (from SM or MN or both); 4) provide mechanistic evidence for whether mitochondrial Ca2+ mishandling is a trigger or a target for disease progression in ALS mice, regardless of the causing mutations (mitochondrial related or non-mitochondrial related); and most importantly, 5) test the validity of a potential new therapeutic target (mitochondrial Ca2+ uptake, or the mitochondrial Ca2+ uniporter) for the treatment of ALS.

肌萎缩性侧索硬化症（ALS）是一种致命的、成人发病的神经退行性疾病，其特征为