TDP-43 was recently identified as one of the major proteins that accumulate in inclusions in sporadic Amyotrophic Lateral Sclerosis (ALS) and in Fronto-temporal dementia with ubiquitin inclusions (FTLD- U). Abnormalities in TDP-43 biology are sufficient to cause neurodegenerative disease because mutations in TDP-43 are linked to familial ALS, which suggests that TDP-43 is linked directly to the disease process. The work in this grant proposal will build on our discovery that TDP-43 regulates the translational response to stress. Neurons respond to stresses, such as occur in neurodegenerative diseases, by entering a state of translational arrest. Translationally silenced mRNA is sequestered into inclusions termed stress granules (SG), which are composed of an mRNA and RNA binding proteins, such as TIA-1. Inclusions composed of SGs are intriguing because of their dynamic nature. The proteins that nucleate SGs have the ability to reversibly aggregate partly because they contain aggregation prone polyglutamine and prion domains. TDP-43 is also a RNA binding protein. Our research demonstrates that TDP-43 co-localizes with SGs, and is essential for SG formation. Disease related mutations in TDP-43 appear to enhance SG formation, and conversely, agents that inhibit SG formation rapidly disaggregate TDP-43 inclusions. Our data also suggests that translational inhibitors can suppress or even rapidly disperse TDP-43 inclusions. We hypothesize that SGs contribute to formation of TDP-43 inclusions, such as occur in FTLD-U and ALS, and that inhibiting SGs can inhibit formation of TDP-43 inclusions.
Aim 1 of this proposal will move our work from cell lines to primary neurons. Our preliminary work has been performed in cell lines such as human BE-M17 neuroblastoma cells, but the regulation of SGs differs in neurons. We will determine the types of conditions that stimulate formation of TDP-43 inclusions in primary cortical and spinal motor neuron cultures. We will also determine how mutations in TDP-43 affect inclusion formation.
Aim 2 will identify the structural domains of TDP-43 inclusion formation and suppression/dispersion of TDP-43 inclusions. This work will identify the conditions and domains on TDP-43 that one can target to develop therapeutic approaches that can suppress or reverse TDP-43 inclusions and possibly treat ALS and FTLD-U.

Public Health Relevance

This project investigates TDP-43, which is one of the major proteins that accumulate in Amyotrophic Lateral Sclerosis (ALS) and in Fronto-temporal dementia with ubiquitin inclusions (FTLD-U). We will determine the types of conditions that stimulate aggregation of TDP-43 and novel methods to prevent or reverse TDP-43 aggregation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS066108-02
Application #
8049654
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2010-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$232,750
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Saha, Shamol; Ash, Peter E A; Gowda, Vivek et al. (2015) Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol Neurodegener 10:26
Liu-Yesucevitz, Liqun; Lin, Amy Y; Ebata, Atsushi et al. (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34:4167-74
Boyd, Justin D; Lee, Peter; Feiler, Marisa S et al. (2014) A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen 19:44-56
Ash, Peter E A; Vanderweyde, Tara E; Youmans, Katherine L et al. (2014) Pathological stress granules in Alzheimer's disease. Brain Res 1584:52-8
McKee, Ann C; Stern, Robert A; Nowinski, Christopher J et al. (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43-64
Ravid, Katya; Wolozin, Benjamin (2013) The Scientist's Pledge. Acad Med 88:743
Vanderweyde, Tara; Youmans, Katie; Liu-Yesucevitz, Liqun et al. (2013) Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review. Gerontology 59:524-33
Rodriguez-Ortiz, Carlos J; Hoshino, Hitomi; Cheng, David et al. (2013) Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice. Am J Pathol 183:504-15
Leung, Amy; Nah, Shirley K; Reid, Whitney et al. (2013) Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis. Stem Cell Reports 1:451-63
Vanderweyde, Tara; Yu, Haung; Varnum, Megan et al. (2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci 32:8270-83

Showing the most recent 10 out of 18 publications