Tar DNA-Binding Protein, 43 kDa, (TDP-43) is a multifunctional DNA/RNA binding protein. TDP-43 Proteinopathy is a heterogeneous spectrum of neurodegenerative disorders that includes cases of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Like other neurodegenerative disorders, TDP-43 proteinopathy represents a substantial societal burden, and yet lacks early diagnostic tools or disease-modifying therapies. Evidence supports the idea that either mutations in or dysregulation of TDP-43 lead to TDP-43 proteinopathy. However, the biological function of TDP-43 and the molecular mechanisms by which TDP-43 leads to TDP-43 proteinopathy remain to be elucidated. One facet that has not been fully explored is the role of microRNAs. MicroRNAs (i.e. miRNAs) are a class of non-coding RNAs that regulate mRNA targets by binding them and destabilizing them. Each miRNA can target dozens of mRNAs, and each mRNA can be targeted by multiple miRNAs. Thus, a complex network of miRNA-mRNA interactions emerges in any cell. Though it is known that TDP-43 regulates miRNA biogenesis, which miRNAs are regulated, what their biological function is, and whether they have a role in the pathogenesis of TDP-43 proteinopathy have not been systematically characterized. To address these questions, this proposal has two aims. In the first aim, miRNA expression profiles will be collected from mouse cortical neurons to determine which miRNAs change after TDP-43 knock-down. Then, paired expression profiles of miRNAs and mRNAs will be collected in this knock-down model, as well as in a cellular mouse model of TDP-43 proteinopathy that the lab has developed, and in post-mortem brain tissue samples from TDP-43 proteinopathy patients. With these paired expression profiles, a bioinformatics approach will then be used to first predict what miRNA-mRNA interactions are occurring. It will then predict which particular miRNAs and mRNAs are having the largest impact on four functional network domains (TDP-43 aggregation, neuronal survival, axonal integrity, and mitochondrial function) dysregulated in TDP-43 proteinopathy. In the second aim, experiments will address whether modulating the interactions of three predicted miRNAs and three target genes will impact the four functional domains. The lab has recently developed a novel microfluidics chamber with a coupled algorithm, which will be utilized to assess axonal integrity in an unbiased and efficient manner. The lab has also established cell biological, imaging and biochemical assays to study the other functional domains. The insights gleaned from these two aims will contribute to a foundation of knowledge about the biological function of TDP-43 and the pathogenesis of TDP- 43 proteinopathy that will help develop early diagnostic tools and disease-modifying therapies.

Public Health Relevance

'TDP-43 proteinopathy' is a spectrum of neurodegenerative disorders that includes a significant proportion of cases of Lou Gehrig's Disease and Frontotemporal Lobar Degeneration, and is thought to be caused by the malfunctioning of a protein called TDP-43. This group of diseases represents a substantial economic and social burden. The goal of this proposal is to study the neuron's network of RNA interactions to understand how TDP-43 influences that network as part of its biological function and in TDP-43 proteinopathy; this will contribute to a foundation of knowledge that could lead to the development of diagnostic tools or disease- modifying therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS090893-04
Application #
9382912
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Gubitz, Amelie
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Chen, Xiaowei; Fan, Zhen; McGee, Warren et al. (2018) TDP-43 regulates cancer-associated microRNAs. Protein Cell 9:848-866
Njoroge, Rose N; Unno, Kenji; Zhao, Jonathan C et al. (2017) Organoids model distinct Vitamin E effects at different stages of prostate cancer evolution. Sci Rep 7:16285
Zhang, Yunjia; Chen, Mengmeng; Qiu, Zilong et al. (2016) MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2. Protein Cell 7:489-500