Mechanisms regulating tau alternative pre-mRNA splicing Accumulating evidence indicates that pre-mRNA splicing defects and aberrant splicing lead to a range of neurodegenerative disorders. Alternative splicing is critical for tau gene function, and splicing mutations in the human tau gene lead to fronto-temporal lobe dementia (FTLD-tau). Although tau splicing mutations were initially reported in 1998, the mechanisms by which mutations affect tau alternative splicing are still poorly understood, and risk factors as well as genetic modifiers in FTLD-tau remain to be identified. This proposal aims to investigate the mechanisms regulating tau gene alternative splicing. We plan to use molecular, biochemical and cell biological methods to investigate tau alternative splicing and to compare the differential spliceosomal recognition of wild type versus mutant tau transcripts. We have established both in vitro biochemical assays and cell culture systems to investigate tau exon 10 alternative splicing. Using biochemical assays and an expression cloning strategy, we have identified several proteins involved in tau exon 10 alternative splicing in our preliminary studies. A primary neuronal culture system has also been set up to investigate the role of identified factors in neuronal cell death. Molecular dissection of cis- and trans-acting elements important for tau alternative splicing will not only help in understanding the basic mechanisms controlling tau alternative splicing but also reveal new players in pathogenesis of neurodegeneration. We plan to use combined bioinformatics, biochemical, molecular and genetic approaches to study the pathogenetic mechanisms underlying FTLD-tau, one most common neurodegenerative disorders.

Public Health Relevance

Overwhelming evidence supports that aberrant RNA processing plays an important role in the pathogenesis of neurodegeneration, including tauopathy, a common neurological disease. Splicing mutations affecting tau pre-mRNA splicing lead to tauopathy, however, the majority of tauopathy patients show disturbance in tau pre-mRNA splicing regulation without detectable mutations in the tau gene. The mechanisms by which mutations affect tau alternative splicing are poorly understood, and risk factors as well as genetic modifiers in tauopathy remain to be identified. Based on published work and our preliminary studies, we propose to use a combined molecular, biochemical and cell biological approach to investigate how mutations affecting tau alternative splicing and to identify possible risk factors or genetic modifiers that contribute to pathogenesis of tauopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033004-04
Application #
8726259
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Marilyn
Project Start
2011-08-15
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$312,625
Indirect Cost
$107,625
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Chen, Mengmeng; Li, Yang; Yang, Mengxue et al. (2016) A new method for quantifying mitochondrial axonal transport. Protein Cell 7:804-819
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
Chen, Yanbo; Deng, Jianwen; Wang, Peng et al. (2016) PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration. Hum Mol Genet 25:5059-5068
Kong, Ruirui; Yi, Fengshuang; Wen, Pushuai et al. (2015) Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression. J Clin Invest 125:4407-20
Deng, Jianwen; Yang, Mengxue; Chen, Yanbo et al. (2015) FUS Interacts with HSP60 to Promote Mitochondrial Damage. PLoS Genet 11:e1005357
Li, Yang; Yang, Mengxue; Huang, Zhuo et al. (2014) AxonQuant: A Microfluidic Chamber Culture-Coupled Algorithm That Allows High-Throughput Quantification of Axonal Damage. Neurosignals 22:14-29
Wen, Pushuai; Kong, Ruirui; Liu, Jianghong et al. (2014) USP33, a new player in lung cancer, mediates Slit-Robo signaling. Protein Cell 5:704-13
Zhu, Li; Xu, Meng; Yang, Mengxue et al. (2014) An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel ?-structure and induces TDP-43 redistribution. Hum Mol Genet 23:6863-77
Bigio, Eileen H; Wu, Jane Y; Deng, Han-Xiang et al. (2013) Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid. Acta Neuropathol 125:463-5
Xu, Meng; Zhu, Li; Liu, Jianghong et al. (2013) Characterization of ?-domains in C-terminal fragments of TDP-43 by scanning tunneling microscopy. J Struct Biol 181:11-6

Showing the most recent 10 out of 17 publications