For many neurodegenerative diseases, both effective treatments and underlying causes are unknown. A specific protein, TDP-43, has recently been shown to be abnormally deposited in multiple neurodegenerative diseases, including Amyotropic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia (FTLD). TDP-43 (TARDBP) is a conserved, broadly expressed nuclear protein with demonstrated roles in mRNA splicing and stability. By analogy with other neurodegenerative diseases associated with specific protein inclusions or aggregates (e.g., huntingtin in Huntington's, 1-synuclein in Parkinson's, 1-amyloid peptide in Alzheimer's, etc.), there are good reasons to believe that TDP-43 plays a causal role in neurodegenerative pathology. We have expressed human TDP-43 in C. elegans in order to assess the effects of TDP-43 overexpression in an in vivo model. Our experiments show that transgenic worms with neuronal expression of human TDP-43 have an uncoordinated movement phenotype that is indicative of neuronal dysfunction. Thus, our data support a neurotoxic role for TDP-43. The molecular mechanism(s) by which TDP-43 may be neurotoxic are unclear, in part because the full range of TDP-43 function is unknown. TDP-43-positive inclusions occur in FTLD cases caused by loss-of-function mutations in progranulin but the biological connection between TDP-43 and progranulin has not been established. In this project, we will seek to identify the conserved functions of TDP-43 (and progranulin), and the molecular and cellular mechanisms by which TDP-43 causes neurodegeneration. Specifically, we will carefully characterize C. elegans strains with deletions of TDP-43 and progranulin to determine the functions of these genes at the organismal level. We will also generate and characterize a series of transgenic C. elegans strains expressing variants of human TDP-43 designed to elucidate the molecular mechanisms of TDP-43 toxicity. These transgenic strains will also be used in forward genetic screens to identify components of the TDP-43 neurotoxic pathway. The C. elegans studies will be complemented by parallel cell culture studies, which will serve to validate and extend findings made in the C. elegans model system.

Public Health Relevance

For many neurodegenerative diseases, both effective treatments and underlying causes are unknown. A specific protein, TDP-43, has recently been shown to be abnormally deposited in multiple neurodegenerative diseases, including Amyotropic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia (FTLD). In this project we will use model systems to determine the functions of TDP-43 and how its deposition may cause neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063964-05
Application #
8453483
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$314,342
Indirect Cost
$74,578
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Zhang, Yong-Jie; Jansen-West, Karen; Xu, Ya-Fei et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505-24
Cook, Casey; Carlomagno, Yari; Gendron, Tania F et al. (2014) Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet 23:104-16
D'Alton, Simon; Altshuler, Marcelle; Cannon, Ashley et al. (2014) Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling. PLoS One 9:e86513
Cook, Casey; Dunmore, Judy H; Murray, Melissa E et al. (2014) Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging 35:1769-77
Gendron, Tania F; Belzil, Veronique V; Zhang, Yong-Jie et al. (2014) Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127:359-76
Lee, Wing C; Almeida, Sandra; Prudencio, Mercedes et al. (2014) Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet 23:1467-78
Bieniek, Kevin F; van Blitterswijk, Marka; Baker, Matthew C et al. (2014) Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia. JAMA Neurol 71:775-81
Carlomagno, Yari; Zhang, Yongjie; Davis, Mary et al. (2014) Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins. PLoS One 9:e90452
Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50
Zhang, Yong-Jie; Caulfield, Thomas; Xu, Ya-Fei et al. (2013) The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum Mol Genet 22:3112-22

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