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In vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathies

TDP-43 蛋白病中 stathmin-2 缺失的体内建模和治疗开发

基本信息

批准号：
10317404
负责人：
Don W Cleveland
金额：
$ 250.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317404
关键词：
Adult Affect Alleles Alzheimer&apos s disease patient Amyotrophic Lateral Sclerosis Animal Model Animals Antisense Oligonucleotides Axon Axotomy Binding Binding Proteins Binding Sites C9ORF72 Chronic Cognition Disorders Collaborations Cytoplasm Disease Frontotemporal Dementia Genes Genetically Engineered Mouse Human Industrialization Inherited Injections Introns Lead Maintenance Mediating Messenger RNA Modeling Molecular Motor Motor Neurons Mus Mutation Natural regeneration Nerve Degeneration Nerve Regeneration Nervous system structure Neurodegenerative Disorders Neuromuscular Junction Neurons Nuclear PGRN gene Pathogenesis Pathologic Pathology Patients Phenotype Polyadenylation Pre-Clinical Model Proteins RNA RNA Processing RNA Splicing RNA-Binding Proteins Regenerative capacity Rodent Role Site Spinal Cord Testing Therapeutic Tissues Transcript alpha Tubulin axon regeneration base falls familial amyotrophic lateral sclerosis frontotemporal lobar dementia-amyotrophic lateral sclerosis genome editing granulin humanized mouse in vivo in vivo Model in vivo evaluation induced pluripotent stem cell insight loss of function mRNA Precursor model development motor deficit mouse genome mouse model nervous system disorder neuronal growth novel therapeutic intervention premature prevent programs protein TDP-43 restoration small hairpin RNA sporadic amyotrophic lateral sclerosis stathmin therapeutic development therapeutic effectiveness therapeutic evaluation therapy development

项目摘要

PROJECT SUMMARY TDP-43 proteinopathies represent a set of neurological disorders characterized by relocalization of the RNA- binding protein TDP-43 from its native nuclear compartment to the cytoplasm where it accumulates into aggregates. TDP-43 pathology is found in more than 95% of patients with amyotrophic lateral sclerosis (ALS), approximately half of frontotemporal dementia (FTD) cases, and more than 30% of Alzheimer’s disease patients. TDP-43 is involved in fundamental RNA processing activities and binds thousands of transcripts to regulate their expression, splicing and transport. We and others have recently identified a critical role for TDP-43 in regulating the expression of the neuronal growth-associated factor stathmin-2, a tubulin-binding protein involved in axon outgrowth and regeneration. TDP-43 disruption induces truncation (by aberrant splicing and premature polyadenylation) of stathmin-2 pre-mRNA, thereby silencing stathmin-2 when TDP-43 nuclear levels fall. Stathmin-2 is suppressed in affected neurons from the vast majority of ALS/FTD patients, and the neuronal regeneration capacity of iPSC-derived motor neurons with TDP-43 depletion can be rescued by increasing levels of STMN2. Notably, while stathmin-2 is the human mRNA most affected by reduction in TDP-43, the stahmin-2 pre-mRNA is neither bound nor regulated by TDP-43 in rodents, a major caveat for animal modeling of TDP-43 proteinopathies. Here we propose to use newly generated mouse models to determine whether inactivated (Aim 1) or humanized stathmin-2 (Aim 2) alleles synergize with TDP-43, progranulin, or C9ORF72 ALS/FTD mutations to drive motor neuron or cognitive disease. While evidence supports that stathmin-2 is essential for axonal regeneration, the contribution of stathmin-2 loss in neurodegeneration remains to be determined. We propose an ambitious program to establish the impact of in vivo stathmin-2 reduction in TDP-43 proteinopathies. Mouse models generated in this project will recapitulate a major molecular alteration associated with TDP-43 proteinopathy and represent an important platform for therapeutic development in ALS/FTD. In addition, recognizing that restoration of stathmin-2 level is an attractive strategy with broad implications in neurodegenerative diseases, we will test the therapeutic potential of antisense oligonucleotides (ASO) that prevent aberrant splicing of Stmn2 (Aim 3). This collaborative effort has the potential to uncover new insights on the contribution of stathmin-2 loss in neurodegeneration, to generate new preclinical models, and to develop a novel therapeutic strategy for ALS and FTD.

项目总结